Tetrasubstituted benzenes

ABSTRACT

Tetrasubstituted benzenes that act as modulators of gamma secretase and their use in the treatment of one or more symptoms of treating neurodegenerative disorders, e.g., Alzheimer&#39;s disease, are described.

RELATED APPLICATION INFORMATION

This application is a continuation of U.S. patent application Ser. No.12/341,201, filed Dec. 22, 2008, now U.S. Pat. No. 8,217,064, whichclaims priority to U.S. provisional application Ser. No. 61/015,605,filed Dec. 20, 2007, and to U.S. provisional application Ser. No.61/109,665, filed Oct. 30, 2008, all of which are herein incorporated byreference.

BACKGROUND

Alzheimer's disease (AD) is the most prevalent form of dementia. It is aneurodegenerative disorder that is associated (though not exclusively)with aging. The disorder is clinically characterized by a progressiveloss of memory, cognition, reasoning and judgment that leads to anextreme mental deterioration and ultimately death. The disorder ispathologically characterized by the deposition of extracellular plaquesand the presence of neurofibrillary tangles. These plaques areconsidered to play an important role in the pathogenesis of the disease.

These plaques mainly comprise of fibrillar aggregates of β-amyloidpeptide (Aβ), which are products of the amyloid precursor protein (APP),a 695 amino-acid protein. APP is initially processed by β-secretaseforming a secreted peptide and a membrane bound C99 fragment. The C99fragment is subsequently processed by the proteolytic activity ofγ-secretase. Multiple sites of proteolysis on the C99 fragment lead tothe production of a range of smaller peptides (Aβ 37-42 amino acids).N-terminal truncations can also be found e.g. Aβ (4-42, 11-42) forconvenience Aβ40 and Aβ42 as used herein incorporates these N-terminaltruncated peptides. Upon secretion, the Aβ peptides initially formsoluble aggregates which ultimately lead to the formation of insolubledeposits and plaques. Aβ42 is believed to be the most neurotoxic, theshorter peptides have less propensity to aggregate and form plaques. TheAβ plaques in the brain are also associated with cerebral amyloidangiopathy, hereditary cerebral hemorrhage with amyloidosis, multiinfarct dementia, dementia pugilistisca, inclusion body myositis andDown's Syndrome.

γ-secretase is an association of four proteins: Aph1, Nicastrin,Presenillin and Pen-2 (review De Strooper 2003, Neuron 38, 9). Aβ42 isselectively increased in patients carrying particular mutations in oneof these components, presenilin. These mutations are correlated withearly onset a familial AD. Inhibition of γ-secretase resulting in thelowering of Aβ42 is a desirable activity for the pharmaceuticalcommunity and numerous inhibitors have been found, e.g., Thompson et at(Bio. Org. and Med. Chem. Letters 2006, 16, 2357-63), Shaw et al (Bio.Org. and Med. Chem. Letters 2006, 17, 511-16) and Asberom et at (Bio.Org. and Med. Chem. Letters 2007, 15, 2219-2223). Inhibition ofγ-secretase though is not without side-effects, some of which are due tothe γ-secretase complex processing substrates other than C99, for e.g.Notch. A more desirable approach is to modulate the proteolytic activityof the γ-secretase complex in a manner that lowers Aβ42 in favor ofshorter peptides without significantly affecting the activity ofγ-secretase on substrates such as Notch.

Compounds that have shown modulation of γ-secretase include certainnon-steroidal, anti-inflammatory drugs (NSAIDs), for exampleFlurbiprofen, (Stock et at Bio. Org. and Med. Chem. Letters 2006, 16,2219-2223). Other publications that disclose agents said to reduce Aβ42through the modulation of γ-secretase include: WO 04/074232, WO05/054193, Perreto et at Journal of Medicinal Chemistry 2005, 485705-20, WO05/108362, WO 06/008558, WO 06/021441, WO 06/041874, WO06/045554, WO04110350, WO 06/043964, WO 05/115990, EP1847524, WO07/116,228, WO 07/110,667, WO 07/124,394, EP184752, EP 01849762, WO07/125,364.

SUMMARY

Described herein are tetrasubstituted benzene compounds of formulas (I)and (II) and pharmaceutically acceptable salts thereof

Wherein:A is CO₂H or tetrazole;R₁ and R₂ are independently selected from: (a) H, (b) F, (c) OH, (d)OR₆, (e) SR₆, (f) NHR₇, (g) N(R₇)₂ (h) NHC(O)R₆, (i) NHCO₂R₆, (j)(C₂-C₆)alkyl, (k) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, (l) C₁-C₆ alkyl thatis independently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂—groups, (m) (C₃-C₇)cycloalkyl, (n) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, (o)heterocycloalkylalky and (p) (CH₂)_(n)Q wherein n=0-2 and wherein Q is amono- or bicyclic aromatic or heteroaromatic ring system having 5 to 10ring atoms independently selected from C, N, O and S, provided that notmore than 3 ring atoms in any single ring are other than C, and whereinQ is optionally independently substituted with up to 3 groups selectedfrom alkyl, halogen, CF₃, OH, OCF₃, alkoxy, OCH₂CH₂OCH₃, NH₂,alkylamino, dialkylamino, morpholino, CN, NO₂, alkylthio andalkylsulfonyl,

and wherein each alkyl or cycloalkyl of R₁ and R₂ is optionallyindependently substituted with one or more halo, hydroxy, oxo, cyano,CF₃, C₁-C₄ alkyl,

provided that both R₁ and R₂ are not H,

or

R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl orheterocycloalkyl ring which is optionally independently singly ormultiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl

or

R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ringsubstituted with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together toform a 3-7 membered cycloalkyl ring wherein each cycloalkyl isoptionally independently singly or multiply substituted with halo,hydroxy, oxo, cyano, CF₃, C₁-C₄ alkylR₆ is selected from:

(a) C1-C6 alkyl optionally and independently interrupted by one or more—O—, —S—, —S(O), or —S(O)₂— groups,

(b) (C₃-C₇)cycloalkyl,

(c) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, (d) heterocycloalkylalky and

(e) (CH₂)_(n)Q wherein n=0-2 and wherein Q is a mono- or bicyclicaromatic or heteroaromatic ring system having 5 to 10 ring atomsindependently selected from C, N, O and S, provided that not more than 3ring atoms in any single ring are other than C, and wherein Q isoptionally independently substituted with up to 3 groups selected fromalkyl, halogen, CF₃, OH, OCF₃, alkoxy, OCH₂CH₂OCH₃, NH₂, alkylamino,dialkylamino, morpholino, CN, NO₂, alkylthio and alkylsulfonyl;

R₇ is independently chosen from alkyl, alkoxyethyl, cycloalkyl,cycloalkylalkyl, heterocycloalkylalkyl or (CH₂)_(n)Q, wherein n=0-2 andwherein Q is a mono or bicyclic aromatic or heteroaromatic ring systemhaving 5 to 10 ring atoms independently selected from C, N, O and S,provided that not more than 3 ring atoms in any single ring are otherthan C and wherein Q is optionally substituted with up to 3 groupsindependently selected from alkyl, halogen, CF₃, OH, OCF₃, alkoxy,OCH₂CH₂OCH₃, NH₂, alkylamino, dialkylamino, morpholino, CN, NO₂,alkylthio, alkylsulfonyl; or in the case when two R₇ are attached to thesame N and are both alkyl, they can be taken together to form a5-membered or 6-membered ring optionally containing O, S, N(H) orN-alkyl;

X is a bond or a divalent linking group selected from —O—, —OCH₂—,—OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—,—CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S—, —CH₂SCH₂—, —C(O)NH—,—C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—, —S(O₂)—, —S(O)₂N(H)—,—S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— wherein the point of attachmentof divalent linking groups, X, to R₃ in the Formulas I and II is to theright;

Y is a bond or a divalent linking group selected from —O—, —OCH₂—,—OCH(R₇), —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—,—CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S—, —CH₂SCH₂—, —C(O)NH—,—C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—, —S(O₂)—, —S(O)₂N(H)—,—S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— wherein the point of attachmentof divalent linking groups, Y, to R₄ in the Formulas I and II is to theright;R₃ is (a) C₁-C₇ alkyl optionally and independently interrupted by one ormore —O—, —S—, —S(O)—, and —S(O)₂— groups,

(b) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl,

(c) heterocycloalkylalkyl, or

(d) a group Z, wherein Z is a mono- or bi-cyclic ring system having 3 to10 ring atoms independently selected from C, N, O and S, provided thatnot more than 3 ring atoms in any single ring are other than C, saidring system optionally bearing up to 3 substituents independentlyselected from halogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy, aryloxy,heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂,SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆,N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂,C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. In the case where R₃is a mono- or bi-cyclic ring system having 5 to 10 ring atoms, theattachment site may be either at a carbon atom or a nitrogen atom of themono- or bi-cyclic ring system provided that only three bonds are madeto nitrogen;

R₄ is a (a) C₁-C₇ alkyl group optionally and independently interruptedby one or more —O—, —S—, —S(O)—, or —S(O)₂— groups,

(b) (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl,

(c) heterocycloalkylalkyl or

(d) a group Z, wherein Z is a mono- or bi-cyclic ring system having 5 to10 ring atoms independently selected from C, N, O and S, provided thatnot more than 3 ring atoms in any single ring are other than C, saidring system optionally bearing up to 3 substituents independentlyselected from halogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy, aryloxy,heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂,SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆,N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂,C(O)NH2, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. In the case where R₄is a mono- or bi-cyclic ring system having 5 to 10 ring atoms, theattachment site may be either at a carbon atom or a nitrogen atom of themono- or bi-cyclic ring system provided that only three bonds are madeto nitrogen; and

R₅ is selected from: NO₂, NH₂, aryl, heteroaryl, F, Cl, Br, CN, OH,C₁-C₄ alkoxy, SR₆, S(O)₂R₆, S(O)₂N(R₇)₂, (C₁-C₄) alkyl,(C₀-C₃)alkyl-(C₃-C₇) cycloalkyl, —O—(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, and(C₂-C₄) alkynyl, wherein each alkyl or cycloalkyl is optionallyindependently substituted with one or more halo, hydroxy, oxo, cyano,CF₃, C₁-C₄ alkylprovided that one or both of R₃ and R₄ is Z.

In one embodiment R₁ and R₂ are taken together form a 3-7 memberedcycloalkyl or heterocycloalkyl ring. In another embodiment R₁ ishydrogen and R₂ is F, R₆, OH, OR₆, SR₆, NHR₇, N(R₇)₂NHC(O)R₆, NHCO₂R₆wherein R₆ and R₇ are as defined previously. In a further embodiment R₁is hydrogen and R₂ is R₆, OR₆ or SR₆. In an additional embodiment R₁ ishydrogen and R₂ is alkyl, alkoxy or thioalkyl. In another embodiment R₁is hydrogen and R₂ is R₆. In a further embodiment R₁ is hydrogen and R₂is C1-C4 alkyl.

In one embodiment X is a bond. In another embodiment X is a divalentlinking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—,—C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—,CH₂S—, —CH₂SCH₂—, —C(O)NH—, —C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—,—S(O₂)—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— whereinthe point of attachment of divalent linking groups, X, to R₃ in theFormulas I and II is to the right. In another embodiment X is —O—,—OCH₂—, —OCH(R₇)—, CH₂O—, —S—, —S(O)₂—, —S(O)₂N(H)—, —S(O)₂N(R₇)—,—C(O)NH— or —C(O)N(R₇)—. In a further embodiment X is —O—, —S(O)₂—,—S(O)₂N(H)— or —S(O)₂N(R₇)—. In another embodiment X is —O— or —S(O)₂—.

In one embodiment Y is a bond. In another embodiment Y is a divalentlinking group selected from —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—,—C(O)—, —CH═CH—, —CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—,CH₂S—, —CH₂SCH₂—, —C(O)NH—, —C(O)N(R₇)—, —NHC(O)—, —N(R₇)C(O)—, —S(O)—,—S(O₂)—, —S(O)₂N(H)—, —S(O)₂N(R₇)—, —N(H)S(O)₂—, —N(R₇)S(O)₂— whereinthe point of attachment of divalent linking groups, X, to R₃ in theFormulas I and II is to the right. In another embodiment Y is —O—,—OCH₂—, —OCH(R₇)—CH₂O—, —S—, —S(O)₂—, —S(O)₂N(H)—, —S(O)₂N(R₇)—,—C(O)NH—or —C(O)N(R₇)—. In a further embodiment Y is —O—, —S(O)₂—,—S(O)₂N(H)— or —S(O)₂N(R₇)—. In another embodiment Y is —O— or —S(O)₂—.

In one embodiment R₃ is a C1-C7 alkyl group optionally interrupted by—O—, —S—, —S(O)—, or —S(O)₂— groups. In another embodiment R₃ is a C1-C7alkyl group. In a further embodiment R₃ is a C1-C4 alkyl group examplesinclude but are not limited to methyl, ethyl, cyclopropylmethyl,trifluoroethyl. In another embodiment R₃ is a cycloalkylalkyl group withexamples including but not limited to cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In anotherembodiment R₃ is heterocycloalkylalkyl. In another embodiment R₃ is agroup Z as defined above wherein

Z is a mono- or bi-cyclic ring system having 5 to 10 ring atomsindependently selected from C, N, O and S, provided that not more than 3ring atoms in any single ring are other than C, said ring systemoptionally bearing up to 3 substituents independently selected fromhalogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆,S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆,NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂,C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. In the latter embodiment Zcomprises mono- or bi-cyclic ring system ring systems that furthermoremay be fully saturated, partially saturated or aromatic. Examples ofmonocyclic ring systems that are fully saturated include but are notlimited to 5-6 membered ring systems such as cyclohexyl, cyclopentanyl,piperazinyl, tetrahydrofuranyl and piperidinyl. Examples of monocyclicring systems that are partially saturated include but are not limited to5-6 membered ring systems such as cyclohexenyl, cyclopentenyl,dihydrofuranyl and tetrahydropyridinyl. piperidinyl. Examples ofmonocyclic ring systems that are aromatic include but are not limited to5-6 membered ring systems such as phenyl, pyridyl, pyrimidyl,pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl, thiadizolyl, triazolyl,oxazolyl and thiazolyl. Examples of bicyclic ring systems that are fullysaturated include but are not limited to 9-10 membered bicyclic ringsystems such as decalinyl, decahydroquinolinyl anddecahydroisoquinolinyl. Examples of bicyclic ring systems that arepartially saturated include but are not limited to 9-10 memberedbicyclic ring systems such as tetrahydronapthyl, tetrahydroquinolinyland tetrahydroisoquinolinyl. Examples of bicyclic ring systems that arearomatic include but are not limited to 9-10 membered bicyclic ringsystems such as napthyl, indolyl, indazolyl, benzimidazolyl,benzthiadiazolyl and imidazopyridinyl. In one further embodiment themono- or bi-cyclic ring system ring system comprises up to 2 nitrogenatoms and up to 1 sulfur or oxygen atoms.

In one embodiment R₄ is a C1-C7 alkyl group optionally interrupted by—O—, —S—, —S(O)—, or —S(O)₂— groups. In another embodiment R₄ is a C1-C7alkyl group. In a further embodiment R₄ is a C1-C4 alkyl group examplesinclude but are not limited to methyl, ethyl, cyclopropylmethyl,trifluoroethyl. In another embodiment R₄ is a cycloalkylalkyl group withexamples including but not limited to cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In anotherembodiment R₄ is heterocycloalkylalkyl. In another embodiment R₄ is agroup Z as defined above wherein Z is a mono- or bi-cyclic ring systemhaving 5 to 10 ring atoms independently selected from C, N, O and S,provided that not more than 3 ring atoms in any single ring are otherthan C, said ring system optionally bearing up to 3 substituentsindependently selected from halogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy,aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇,OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂,NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇),N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. Inthe latter embodiment Z comprises mono- or bi-cyclic ring system ringsystems that furthermore may be fully saturated, partially saturated oraromatic. Examples of monocyclic ring systems that are fully saturatedinclude but are not limited to 5-6 membered ring systems such ascyclohexyl, cyclopentanyl, piperazinyl, tetrahydrofuranyl andpiperidinyl. Examples of monocyclic ring systems that are partiallysaturated include but are not limited to 5-6 membered ring systems suchas cyclohexenyl, cyclopentenyl, dihydrofuranyl and tetrahydropyridinyl.piperidinyl. Examples of monocyclic ring systems that are aromaticinclude but are not limited to 5-6 membered ring systems such as phenyl,pyridyl, pyrimidyl, pyrrazolyl, thiophene-yl, furanyl, oxadiazolyl,thiadizolyl, triazolyl, oxazolyl and thiazolyl. Examples of bicyclicring systems that are fully saturated include but are not limited to9-10 membered bicyclic ring systems such as decalinyl,decahydroquinolinyl and decahydroisoquinolinyl. Examples of bicyclicring systems that are partially saturated include but are not limited to9-10 membered bicyclic ring systems such as tetrahydronapthyl,tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of bicyclicring systems that are aromatic include but are not limited to 9-10membered bicyclic ring systems such as napthyl, indolyl, indazolyl,benzimidazolyl, benzthiadiazolyl and imidazopyridinyl. In one furtherembodiment the mono- or bi-cyclic ring system ring system comprises upto 2 nitrogen atoms and up to 1 sulfur or oxygen atoms.

Other embodiments include compounds of Formulas III, IV, V, and VI andpharmaceutically acceptable salts thereof wherein R₁, R₂, R₃, R₄, R₅, X,Y and Z are as defined above.

Other embodiments include compounds of Formulas VII, VIII, IX, and X andpharmaceutically acceptable salts thereof wherein R₁, R₂, R₃, R₄, R₅, X,Y and Z are as defined above.

Other embodiments include compounds of Formulas III, IV, V, and VIwherein R₂, R₃, R₄, R₅, X, Y and Z are as defined above and R₁ ishydrogen. Other embodiments include compounds of Formulas III, IV, V,and VI wherein R₃, R₄, R₅ and Z are as defined above; R₁ is hydrogen andR₂ is C1-C4 alkyl.

Other embodiments include compounds of Formulas III, IV, V, and VIwherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Yare independently chosen from a bond, —O—, —OCH₂—, —C(O)—, —S—, —S(O)₂—,—S(O)₂N(R₇)— and —N(R₇)S(O)₂—. Other embodiments include compounds ofFormulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅, and Z are asdefined above and X and Y are independently chosen from a bond, —O—,—S(O)₂— and —S(O)₂N(R₇). Another embodiment comprises compounds ofFormulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅, and Z are asdefined above and X and Y are independently chosen from a bond, —O— andS(O)₂N(R₇). A further embodiment comprises compounds of Formulas III,IV, V, and VI wherein R₁, R₂, R₃, R₄, R₅, and Z are as defined above andX and Y are independently chosen from a bond and —O—.

Other embodiments include compounds of Formulas III, IV, V, and VIwherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ andare independently chosen from a C1-C7 alkyl optionally and independentlyinterrupted by one or more —O—, —S—, —S(O)—, and —S(O)₂— groups,cycloalkylalkyl and heterocycloalkylalkyl. Other embodiments includecompounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₅, X, Y and Zare as defined above and R₃ and R₄ and are independently chosen fromC1-C4 alkyl and cyclopropylmethyl. Other embodiments include compoundsof Formulas III, IV, V, and VI wherein R₁, R₂, R₅, Z are as definedabove and X, Y and are independently chosen from a bond, —S—, —SO₂— and—O— and R₃ and R₄ and are independently chosen from C1-C4 alkyl andcyclopropylmethyl. Other embodiments include compounds of Formulas III,IV, V, and VI wherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃and R₄ and are independently chosen from a group Z wherein Z is asdefined above.

Other embodiments include compounds of Formulas III, IV, V, and VIwherein R₁, R₂, R₃, R₄ and R₅, X and Y are as defined above and Z is aphenyl ring bearing up to 3 substituents independently selected fromhalogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆,S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆,NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH2,C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. Other embodiments includecompounds of Formulas III, IV, V, and VI wherein R₁, R₂, R₃, R₄ and R₅,X and Y are as defined above, and Z is a mono- or bi-cyclic ring systemhaving 5 to 10 ring atoms independently selected from C, N, O and S,provided that not more than 3 ring atoms in any single ring are otherthan C, said ring system optionally bearing up to 3 substituentsindependently selected from halogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy,aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇,OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂,NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇),N(R₇)C(O)NH(R₇)₂, C(O)NH2, C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆.

Other embodiments include compounds of Formulas III, IV, V, and VIwherein R₁, R₂, R₃, R₄X, Y and Z are as defined above and R₅ is NO₂,NH₂, F, Cl, Br, CN, OH, C1-C4 alkoxy, SR₆, S(O)₂R₆ or S(O)₂N(R₇)₂. Otherembodiments include compounds of Formulas III, IV, V, and VI wherein R₁,R₂, R₃, R₄X, Y and Z are as defined above and R₅ is aryl or heteroaryl.Other embodiments include compounds of Formulas III, IV, V, and VIwherein R₁, R₂, R₃, R₄X, Y and Z are as defined above and R₅ is chlorineor fluorine.

Other embodiments include compounds of Formulas VII, VIII, IX, and Xwherein R₂, R₃, R₄, R₅, X, Y and Z are as defined above and R₁ ishydrogen. Other embodiments include compounds of Formulas VII, VIII, IX,and X wherein R₃, R₄, R₅ and Z are as defined above; R₁ is hydrogen andR₂ is C1-C4 alkyl.

Other embodiments include compounds of Formulas VII, VIII, IX, and Xwherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above and X and Yare independently chosen from a bond, —O—, —OCH₂—, —C(O)—, —S—, —S(O)₂—,—S(O)₂N(R₇)— and —N(R₇)S(O)₂—. Other embodiments include compounds ofFormulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, and Z areas defined above and X and Y are independently chosen from a bond, —O—,—S(O)₂— and —S(O)₂N(R₇). Other embodiments include compounds of FormulasVII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ and R₅, and Z are as definedabove and X and Y are independently chosen from a bond, —O— andS(O)₂N(R₇). Other embodiments include compounds of Formulas VII, VIII,IX, and X wherein R₁, R₂, R₃, R₄ and R₅, and Z are as defined above andX and Y are independently chosen from a bond and —O—. Other embodimentsinclude compounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₅,X, Y and Z are as defined above and R₃ and R₄ and are independentlychosen from a C1-C7 alkyl optionally and independently interrupted byone or more —O—, —S—, —S(O)—, and —S(O)₂— groups, cycloalkylalkyl andheterocycloalkylalkyl. Other embodiments include compounds of FormulasIII, IV, V, and VI wherein R₁, R₂, R₅, X, Y and Z are as defined aboveand R₃ and R₄ and are independently chosen from C1-C4 alkyl andcyclopropylmethyl. Other embodiments include compounds of Formulas VII,VIII, IX, and X wherein R₁, R₂, R₅, Z are as defined above and X, Y andare independently chosen from a bond, —S—, —SO₂— and —O— and R₃ and R₄and are independently chosen from C1-C4 alkyl and cyclopropylmethyl.Other embodiments include compounds of Formulas VII, VIII, IX, and Xwherein R₁, R₂, R₅, X, Y and Z are as defined above and R₃ and R₄ andare independently chosen from a group Z wherein Z is as defined above.

Other embodiments include compounds of Formulas VII, VIII, IX, and Xwherein R₁, R₂, R₃, R₄ and R₅, X and Y are as defined above and Z is aphenyl ring bearing up to 3 substituents independently selected fromhalogen, R₆, CF₃, CN, NO₂, OH, C1-C4 alkoxy, aryloxy, heteroaryloxy,OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆, OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆,S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂, NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆,NHC(O)OR₆, N(R₇)C(O)OR₆, N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH2,C(O)NHR₇, C(O)N(R₇)₂, CO₂H, CO₂R₆, COR₆. Other embodiments includecompounds of Formulas VII, VIII, IX, and X wherein R₁, R₂, R₃, R₄ andR₅, X and Y are as defined above, and Z is a mono- or bi-cyclic ringsystem having 5 to 10 ring atoms independently selected from C, N, O andS, provided that not more than 3 ring atoms in any single ring are otherthan C, said ring system optionally bearing ring bearing up to 3substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH,C1-C4 alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆,OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂,NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆,N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H,CO₂R₆, COR₆.

Other embodiments include compounds of Formulas VII, VIII, IX, and Xwherein R₁, R₂, R₄X, Y and Z are as defined above and R₅ is NO₂, NH₂, F,Cl, Br, CN, OH, C1-C4 alkoxy, SR₆, S(O)₂R₆ or S(O)₂N(R₇)₂. Otherembodiments include compounds of Formulas VII, VIII, IX, and X whereinR₁, R₂, R₄X, Y and Z are as defined above and R₅ is aryl or heteroaryl.Other embodiments include compounds of Formulas VII, VIII, IX, and Xwherein R₁, R₂, R₄X, Y and Z are as defined above and R₅ is chlorine orfluorine.

The compounds of formulas I-IX are expected to alter the activity ofγ-secretase and are expected to be useful for the treatment ofAlzheimer's disease and other neurodegenerative disorders.

In another embodiment A is CO₂H.

In another embodiment a compound of formula (I) is selected.

In another embodiment a compound of formula (II) is selected.

In another embodiment a compound of formula (III) is selected.

In another embodiment a compound of formula (IV) is selected.

In another embodiment a compound of formula (V) is selected.

In another embodiment a compound of formula (VI) is selected.

In another embodiment a compound of formula (VII) is selected.

In another embodiment a compound of formula (VIII) is selected.

In another embodiment a compound of formula (IX) is selected.

In another embodiment R₁ and R₂ are independently selected from: H,(C₁-C₆)alkyl, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, C₁-C₆ alkyl that isindependently interrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂—groups or heterocycloalkylalkyl wherein each alkyl or cycloalkyl isoptionally independently singly or multiply substituted with halo,hydroxy, cyano, oxo, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not Hsimultaneously or

R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl orheterocycloalkyl ring which are; optionally independently singly ormultiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl

or

R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ringsubstituted with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together toform a 3-7 membered cycloalkyl ring wherein each cycloalkyl isoptionally independently singly or multiply substituted with halo,hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are independently selected from: H,(C₁-C₆)alkyl, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl wherein each alkyl orcycloalkyl is optionally independently singly or multiply substitutedwith halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ arenot H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H,(C₁-C₆)alkyl, wherein alkyl is optionally independently singly ormultiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkylprovided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H,(C₃-C₆)alkyl, wherein alkyl is optionally independently singly ormultiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkylprovided that R₁ and R₂ are not H simultaneously.

In another embodiment R₁ and R₂ are independently selected from: H,n-propyl, iso-propyl, iso-butyl, n-butyl, iso-pentyl, and n-pentylwherein alkyl is optionally independently singly or multiply substitutedwith halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂are not H simultaneously.

In another embodiment R₁ is H.

In another embodiment R₁ is H and R₂ is n-propyl.

In another embodiment R₁ is H and R₂ is iso-butyl.

In another embodiment R₁ is H and R₂ is n-butyl.

In another embodiment R₁ is H and R₂ is iso-pentyl.

In another embodiment R₁ is H and R₂ is n-pentyl.

In another embodiment R₁ and R₂ are independently selected from: H,(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl wherein cycloalkyl is optionallyindependently singly or multiply substituted with halo, hydroxy, oxo,cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not Hsimultaneously.

In another embodiment R₁ and R₂ are independently selected from: H,(C₀-C₁)alkyl-(C₃-C₇)cycloalkyl wherein cycloalkyl is optionallyindependently singly or multiply substituted with halo, hydroxy, oxo,cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not Hsimultaneously.

In another embodiment R₁ and R₂ are independently selected from: H,(C₀-C₁)alkyl-(C₃-C₅)cycloalkyl wherein cycloalkyl is optionallyindependently singly or multiply substituted with halo, hydroxy, oxo,cyano, CF₃, C₁-C₄ alkyl provided that R₁ and R₂ are not Hsimultaneously.

In another embodiment R₁ is H and R₂ is selected from cyclopentyl,cyclopropylmethyl and cyclobutylmethyl.

In another embodiment R₁ is H and R₂ is cyclopentyl.

In another embodiment R₁ is H and R₂ is cyclopropylmethyl.

In another embodiment R₁ is H and R₂ is cyclobutylmethyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7membered cycloalkyl or heterocycloalkyl ring which are; optionallyindependently singly or multiply substituted with halo, hydroxy, oxo,cyano, CF₃, C₁-C₄ alkyl

or

R₁ and R₂ are taken together to form a 3-7 membered cycloalkyl ringsubstituted with R₂₀ and R₂₁ where R₂₀ and R₂₁ are taken together toform a 3-7 membered cycloalkyl ring wherein each cycloalkyl isoptionally independently singly or multiply substituted with halo,hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7membered cycloalkyl or heterocycloalkyl ring which are; optionallyindependently singly or multiply substituted with halo, hydroxy, oxo,cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7membered cycloalkyl ring which are; optionally independently singly ormultiply substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a cyclopropylring.

In another embodiment R₁ and R₂ are taken together to form a cyclobutylring.

In another embodiment R₁ and R₂ are taken together to form a cyclopentylring.

In another embodiment R₁ and R₂ are taken together to form a cyclohexylring.

In another embodiment R₁ and R₂ are taken together to form a 3-7membered cycloalkyl ring substituted with R₂₀ and R₂₁ where R₂₀ and R₂₁are taken together to form a 3-7 membered cycloalkyl ring wherein eachcycloalkyl is optionally independently singly or multiply substitutedwith halo, hydroxy, oxo, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form a 3-7membered cycloalkyl ring substituted on the same carbon atom with R₂₀and R₂₁ where R₂₀ and R₂₁ are taken together to form a 3-7 memberedcycloalkyl ring wherein each cycloalkyl is optionally independentlysingly or multiply substituted with halo, hydroxy, oxo, cyano, CF₃,C₁-C₄ alkyl.

In another embodiment R₁ and R₂ are taken together to form aspiro[2.3]hexane, a spiro[3.3]heptane or a spiro[3.4]octane ring system.

In another embodiment R₁ and R₂ are taken together to form aspiro[2.3]hexane ring system.

In another embodiment R₁ and R₂ are taken together to form aspiro[3.3]heptane ring system.

In another embodiment R₁ and R₂ are taken together to form aspiro[3.4]octane ring system.

In another embodiment R₁ and R₂ are taken together to form a5,5-disubstituted spiro[2.3]hexane ring system.

In another embodiment R₁ and R₂ are taken together to form a2,2-disubstituted spiro[3.3]heptane ring system.

In another embodiment R₁ and R₂ are taken together to form a2,2-disubstituted spiro[3.4]octane ring system.

In another embodiment R₁ and R₂ are independently selected from: H, F,OH, OR₆, SR₆, NHR₇, N(R₇)₂NHC(O)R₆ or NHCO₂R₆ provided that R₁ and R₂are not H simultaneously.

In another embodiment R₁ and R₂ if not H are unsubstituted, except thatwhen R₁ and R₂ are taken with the carbon to which they are attached formC₃-C₇ ring, the ring may be substituted with R₂₀ and R₂₁, whichthemselves are unsubstituted.

In another embodiment R₁ and R₂ if not H are optionally singly ormultiply independently substituted with halo, hydroxy, oxo, cyano, CF₃,C₁-C₄ alkyl

In another embodiment R₁ and R₂ if not H are singly or multiplyindependently substituted with halo, hydroxy, oxo, cyano, CF₃, C₁-C₄alkyl

In another embodiment R₆ is C1-C6 alkyl optionally and independentlyinterrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂— groups,(C₃-C₇)cycloalkyl, (C₄-C₈) cycloalkylalkyl, heterocycloalkylalkyl.

In another embodiment R₆ is C₁-C₆ alkyl optionally and independentlyinterrupted by one or more —O—, —S—, —S(O)—, or —S(O)₂— groups.

In another embodiment R₆ (C₃-C₇)cycloalkyl.

In another embodiment R₆ is a (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl

In another embodiment R₆ heterocycloalkylalkyl.

In another embodiment R₆ is (CH₂)_(n)Q.

In another embodiment R₆ is —CH₂-Q.

In another embodiment Q is aryl.

In another embodiment Q is heteroaryl.

In another embodiment Q is monocyclic heteroaryl.

In another embodiment Q is bicyclic heteroaryl.

In another embodiment X is a bond or a divalent linking group selectedfrom —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—,—CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S— or —CH₂SCH₂—.

In another embodiment X is a bond or a divalent linking group selectedfrom —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂O—, —CH₂OCH₂—, or —CH₂CH₂O.

In another embodiment X is a bond or a divalent linking group selectedfrom —CH₂—, —C(O)—, —CH═CH— or —CH₂CH₂—

In another embodiment X is a bond or a divalent linking group selectedfrom —S—, —SCH₂—, CH₂S— or —CH₂SCH₂—.

In another embodiment X is a bond or a divalent linking group selectedfrom —O— or —S—.

In another embodiment X is a bond.

In another embodiment X is the divalent linking group —O—.

In another embodiment X is the divalent linking group —S—.

In another embodiment Y is a bond or a divalent linking group selectedfrom —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂—, —C(O)—, —CH═CH—,—CH₂CH₂—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —S—, —SCH₂—, CH₂S— or —CH₂SCH₂—.

In another embodiment Y is a bond or a divalent linking group selectedfrom —O—, —OCH₂—, —OCH(R₇)—, —OCH₂CH₂—, —CH₂O—, —CH₂OCH₂—, or —CH₂CH₂O

In another embodiment Y is a bond or a divalent linking group selectedfrom —CH₂—, —C(O)—, —CH═CH— or —CH₂CH₂—.

In another embodiment Y is a bond or a divalent linking group selectedfrom —S—, —SCH₂—, CH₂S— or —CH₂SCH₂—.

In another embodiment Y is a bond or a divalent linking group selectedfrom —O— or —S—.

In another embodiment Y is a bond.

In another embodiment Y is the divalent linking group —O—.

In another embodiment Y is the divalent linking group —S—.

In another embodiment R₃ is a C₁-C₄ alkyl group.

In another embodiment R₃ is a C₁-C₃ alkyl group.

In another embodiment R₃ is a C₂-C₃ alkyl group.

In another embodiment R₃ is selected from ethyl, n-propyl, iso-propyl,trifluoroethyl, or trifluoropropyl.

In another embodiment R₃ is ethyl.

In another embodiment R₃ is n-propyl.

In another embodiment R₃ is iso-propyl.

In another embodiment R₃ is trifluoroethyl.

In another embodiment R₃ is trifluoropropyl.

In another embodiment R₃ is a (C₄-C₁₀) cycloalkylalkyl group.

In another embodiment R₃ is a (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl group.

In another embodiment R₃ is a (C₃-C₇)cycloalkyl group.

In another embodiment R₃ is a (C₁-C₃)alkyl-(C₃-C₇)cycloalkyl group.

In another embodiment R₃ is a (C₁)alkyl-(C₃-C₇)cycloalkyl group.

In another embodiment R₃ is a (C₁)alkyl-(C₃-C₄)cycloalkyl group.

In another embodiment R₃ is a cyclopropylmethyl group.

In another embodiment R₃ is a cyclobutylmethyl group.

In another embodiment R₃ is heterocycloalkylalkyl group.

In another embodiment R₃ is represented by the group Z.

In another embodiment R₃ is not cyclopropylmethyl

In another embodiment Z is monocyclic.

In another embodiment Z is bicyclic

In another embodiment Z is heteroaryl

In another embodiment Z is unsubstituted heteroaryl

In another embodiment Z is benzo[b]thiophenyl,benzo[c][1,2,5]oxadiazoyl, benzo[c][1,2,5]thiadiazolyl orbenzo[d]thiazolyl

In another embodiment Z is benzo[b]thiophenyl or benzo[d]thiazolyl

In another embodiment Z is benzo[c][1,2,5]oxadiazoyl orbenzo[c][1,2,5]thiadiazolyl

In another embodiment Z is benzo[b]thiophenyl

In another embodiment Z is benzo[c][1,2,5]oxadiazoyl

In another embodiment Z is benzo[c][1,2,5]thiadiazolyl

In another embodiment Z is benzo[d]thiazolyl

In another embodiment Z is aryl

In another embodiment Z is substituted phenyl

In another embodiment Z is 4-substituted phenyl

In another embodiment Z is optionally substituted with up to 3substituents independently selected from halogen, R₆, CF₃, CN, NO₂, OH,C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆,OC(O)NHR₇, OC(O)N(R₇)₂, SR₆, S(O)R₆, S(O)₂R₆, S(O)₂NHR₇, S(O)₂N(R₇)₂,NHR₇, N(R₇)₂, NHC(O)R₆, N(R₇)C(O)R₆, NHC(O)OR₆, N(R₇)C(O)OR₆,N(R₇)C(O)NH(R₇), N(R₇)C(O)NH(R₇)₂, C(O)NH₂, C(O)NHR₇, C(O)N(R₇)₂, CO₂H,CO₂R₆ or COR₆ In another embodiment Z is optionally substituted with upto 3 substituents independently selected from halogen, R₆, CF₃, CN, NO₂,C₁-C₄ alkoxy, aryloxy, heteroaryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆,SR₆, NHR₇, N(R₇)₂CO₂H, CO₂R₆ or COR₆

In another embodiment Z is optionally substituted with up to 3substituents independently selected from halogen, R₆, CF₃, CN, NO₂,C₁-C₄ alkoxy, aryloxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆ or SR₆

In another embodiment Z is optionally substituted with up to 3substituents independently selected from halogen, R₆, CF₃, CN, NO₂,C₁-C₄ alkoxy, OCH₂CH₂OCH₃, OC(O)R₆, OC(O)OR₆ or SR₆

In another embodiment Z is optionally substituted with up to 3substituents independently selected from halogen, C₁-C₆ alkyl,(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, CF₃, C₁-C₄ alkoxy, or SR₆

In another embodiment Z is optionally substituted with up to 3substituents independently selected from F, Cl, C₁-C₃ alkyl,(C₃-C₆)cycloalkyl, CF₃, C₁-C₄ alkoxy, S—(C₁-C₄)alkyl orS—(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl

In another embodiment Z is optionally substituted with up to 3substituents independently selected from F, Cl, C₁-C₃ alkyl,(C₃-C₆)cycloalkyl, CF₃, C₁-C₄ alkoxy, or S—(C₁-C₃)alkyl

In another embodiment Z is substituted CF₃, OCF₃, OCH₂CF₃, F, Cl, SMe,Me, Et, iPr

In another embodiment Z is substituted with F

In another embodiment Z is substituted with Cl

In another embodiment Z is substituted with C₁-C₃ alkyl

In another embodiment Z is substituted with (C₃-C₆)cycloalkyl

In another embodiment Z is substituted with CF₃,

In another embodiment Z is substituted with C₁-C₄ alkoxy

In another embodiment Z is substituted with S—(C₁-C₃)alkyl

In another embodiment R₄ is a C₁-C₇ alkyl group.

In another embodiment R₄ is a C₁-C₄ alkyl group.

In another embodiment R₄ is a C₁-C₃ alkyl group.

In another embodiment R₄ is a C₂-C₃ alkyl group.

In another embodiment R₄ is selected from ethyl, n-propyl, iso-propyl,trifluoroethyl, or trifluoropropyl.

In another embodiment R₄ is ethyl.

In another embodiment R₄ is n-propyl.

In another embodiment R₄ is iso-propyl.

In another embodiment R₄ is trifluoroethyl.

In another embodiment R₄ is trifluoropropyl.

In another embodiment R₄ is a (C₄-C₁₀) cycloalkylalkyl group.

In another embodiment R₄ is a (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl group.

In another embodiment R₄ is a (C₃-C₇)cycloalkyl group.

In another embodiment R₄ is a (C₁-C₃)alkyl-(C₃-C₇)cycloalkyl group.

In another embodiment R₄ is a (C₁)alkyl-(C₃-C₇)cycloalkyl group.

In another embodiment R₄ is a (C₁)alkyl-(C₃-C₄) cycloalkyl group.

In another embodiment R₄ is a cyclopropylmethyl group.

In another embodiment R₄ is a cyclobutylmethyl group.

In another embodiment R₄ is heterocycloalkylalkyl group.

In another embodiment R₄ is represented by the group Z.

In another embodiment R₄ is not cyclopropylmethyl

In another embodiment R₅ is, F, Cl, Br, CN, C₁-C₄ alkoxy, SR₆,(C₁-C₄)alkyl, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkyl or(C₂-C₄)alkynyl, where each alkyl or cycloalkyl is optionallyindependently singly or multiply substituted with halo, hydroxy, cyano,CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is, F, Cl, Br, CN, C₁-C₄ alkoxy, SR₆,(C₁-C₄)alkyl, (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkyl or(C₂-C₄)alkynyl, where each alkyl or cycloalkyl is optionallyindependently singly or multiply substituted with halo, hydroxy, cyano,CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is F, Cl, Br, CN, C₁-C₄ alkoxy, —S—(C₁-C₄)alkylor (C₁-C₄)alkyl, where each alkyl is optionally independently singly ormultiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is F, Cl, Br, CN, C₁-C₃ alkoxy —S—(C₁-C₃)alkylor (C₁-C₃) alkyl, where each alkyl is optionally independently singly ormultiply substituted with halo, hydroxy, cyano, CF₃, C₁-C₄ alkyl.

In another embodiment R₅ is F, Cl, Br or CN.

In another embodiment R₅ is F or Cl.

In another embodiment R₅ is F.

In another embodiment R₅ is Cl.

In another embodiment R₅ is Br.

In another embodiment R₅ is CN.

In another embodiment R₅ is C₁-C₃ alkoxy —S—(C₁-C₃)alkyl or (C₁-C₃)alkyl.

In another embodiment R₅ is C₁-C₃ alkoxy.

In another embodiment R₅ is tri-fluoroethoxy or tri-fluoropropoxy.

In another embodiment R₅ is (C₁-C₃) alkyl.

In another embodiment R₅ is CF₃.

In another embodiment R₅ is —S—(C₁-C₃)alkyl.

In another embodiment R₅ is —S-Me, —S-Et or —S—CH₂CF₃.

In another embodiment R₅ is SR₆.

In another embodiment R₅ is (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl,(C₂-C₄)alkynyl, or —(C₃-C₇)cycloalkyl.

In another embodiment R₅ is (C₀-C₃)alkyl-(C₃-C₇)cycloalkyl.

In another embodiment R₅ is (C₂-C₄)alkynyl.

In another embodiment R₅ is trifluoroethynyl.

In another embodiment R₅ is (C₃-C₇)cycloalkyl.

In another embodiment R₅ is cyclopropyl.

In another embodiment R₅ is NO₂ or NH₂.

In another embodiment R₅ is aryl or heteroaryl.

In another embodiment the compound is a compound selected from examples100-3217.

In another embodiment a racemic compound described in the disclosure isselected.

In another embodiment a single enantiomer of the previous embodiments isselected.

In another embodiment a single enantiomer of configuration (R) of theprevious embodiments is selected.

In another embodiment a single enantiomer of configuration (S) of theprevious embodiments is selected.

In another embodiment a solvate of a compound of formula (I-IX) isselected.

In another embodiment a polymorph of compound of formula (I-IX) isselected.

In a separate embodiment, a pharmaceutical composition comprising of thecompound of the previous embodiments and a pharmaceutically acceptablecarrier.

In a separate embodiment, a method for treating a neurodegenerativedisorder comprising administering to a patient an effective amount ofthe pharmaceutical composition of the previous embodiments.

In another embodiment a method for treating Alzheimer's Diseasecomprising administering to a patient an effective amount of thepharmaceutical composition of the previous embodiments.

In the case compounds of Formula (I-IX) may contain asymmetric centersand exist as different enantiomers or diastereomers. All enantiomers ordiastereomeric forms are embodied herein.

Compounds in the disclosure, e.g., compounds of Formulas I-IX, may be inthe form of pharmaceutically acceptable salts. The phrase“pharmaceutically acceptable” refers to salts prepared frompharmaceutically acceptable non-toxic bases and acids, includinginorganic and organic bases and inorganic and organic acids. Saltsderived from inorganic bases include lithium, sodium, potassium,magnesium, calcium and zinc. Salts derived from organic bases includeammonia, primary (e.g. Tromethamine), secondary and tertiary amines, andamino acids (e.g. Lysine). Salts derived from inorganic acids includesulfuric, hydrochloric, phosphoric, methanesulphonic, hydrobromic. Saltsderived from organic acids include C₁₋₆ alkyl carboxylic acids,di-carboxylic acids and tricarboxylic acids such as acetic acid,propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid,adipic acid and citric acid, and alkylsulfonic acids such asmethanesulphonic, and aryl sulfonic acids such as para-tolouene sulfonicacid and benzene sulfonic acid. For detailed list of slats see P. H.Stahl and C. G. Wermuth (eds.) “Handbook of Pharmaceutical Salts,Properties, Selection and Use” Wiley-VCH (ISBN 3-906390-26-8)

Compounds and pharmaceutically acceptable salts thereof may be in theform of a solvates. This occurs when a compound of formula (I-IX))crystallizes in a manner that it incorporates solvent molecules into thecrystal lattice. Examples of solvents forming solvates are water(hydrates), MeOH, EtOH, iPrOH, and acetone. Formulas I-IX cover allsolvates of the depicted compounds.

Compounds in the disclosure may exist in different crystal forms knownas polymorphs.

Practitioners of the art will recognize that certain chemical groups mayexist in multiple tautomeric forms. The scope of this disclosure ismeant to include all such tautomeric forms. For example, a tetrazole mayexist in two tautomeric forms, 1-H tetrazole and a 2-H tetrazole. Thisis depicted in FIGURE below. This example is not meant to be limiting inthe scope of tautomeric forms.

Practitioners of the art will recognize that certain electrophilicketones, may exist in a hydrated form. The scope of this disclosure isto include all such hydrated forms. For example, a trifluoromethylketone may exist in a hydrated form via addition of water to thecarbonyl group. This is depicted in FIGURE below. This example is notmeant to be limiting in the scope of hydrated forms.

Abbreviations used in the following examples and preparations include:

Aβ Amyloid-beta ABL Aβ lowering Ac acyl (Me—C(O)—) AD Alzheimer'sDisease APP Amyloid Precursor Protein Bn Benzyl b/p brain/plasma BSABovine serum Albumin c Cyclo calcd. Calculated cBu Cylcobutyl c-BuCylcobutyl c_(max) Maximal concentration cPr Cyclopropyl c-PrCyclopropyl CHAPS 3-[3-cholamidopropyl)-dimethyl-ammonio]-1- propanesulfonate CTF Carboxy Terminal Fragment CSF Cerebrospinal fluid DAPTN-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester DCC N.N′, Dicyclohexylcarbodiimide DEA Di-ethylamineDIEA Di-isopropylethyl amine DMAP 4-Dimethylamino Pyridine DMFDimethylformamide DMSO Dimethyl sulfoxide Dppf1,4-Bis(diphenylphosphino) ferrocene EDC1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride EDTAEthylene Diamine Tetra-acetic Acid ELISA Enzyme-Linked Immuno SorbentAssay Et₃N Triethylamine Eq. Equivalent g gram(s) HOBt1-Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography hHour(s) hr Hour(s) i.v or IV. Intravenous KHMDS PotassiumHexamethydisilazide LC-MS Liquid Chromatography-Mass Spectrometry LDALithium Di-isopropylamide m Multiplet MeOH Methyl Alcohol or Methanol mmeta mcpba meta-chloro perbenzoic acid min Minute(s) mmol millimolesmmole millimoles ul Microliter μl microliter Ms Mesylate MS MassSpectrometry MW Molecular Weight (all values are ± 0.05) n normal NBSN-Bromosuccinimide NCS N-Chlorosuccinimide NIS N-Iodosuccinimide NMRNuclear Magnetic Resonance NMM N-Methyl Morpholine NSAIDS Non-SteroidalAnti-Inflammatory Drugs o ortho o/n overnight p para PBS PhosphateBuffered Saline PEPPSI1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride PhNTf₂ 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide POPd Dihydrogendichlorobis(di-tert-butylphosphinito-kp) palladate (2-) p.s.i. Poundsper square inch PPAA 1-Propanephosphonic Acid Cyclic Anhydride PyBOP ®Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate PKPharmacokinetics RT (or rt) room temperature (about 20-25° C.) s Singletsat. Saturated sec secondary t Triplet tert tertiary TBAF Tetra-butylammonium fluoride TFA Trifluoroacetic Acid THF Tetrahydrofuran TMB 3,3′5, 5′ Tetramethylbenzidine TMS Trimethylsilyl Tf Triflate Ts Tosylatev/v volume/volume wt/v weight/volume

DESCRIPTION OF THE FIGURE

FIG. 1 demonstrates the desirable effect on Aβ after the administrationof example 1301(2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoicacid) to in C57BL/6 mice when give one dose at 30 mg/kg in a SolutolHS15:Ethanol:Water (15:10:75) formulation (measuring Aβ at 3 hours).

DETAILED DESCRIPTION

Described below are compounds within Formulas I and II as well asmethods for preparing the compounds and using the compounds to treat oneor more symptoms of Alzheimer's disease. The compounds of the disclosureare gamma secretase modulators (GSMs), i.e., compounds that act to shiftthe relative levels of Aβ peptides produced by γ-secretase. In somecases the compounds alter the relative levels of Aβ peptides produced byγ-secretase without significantly changing the total level of Aβpeptides produced.

General Reaction Schemes

The tetrasubstituted benzene compounds of Formulas I and II may beprepared by multistep organic synthetic routes from knownfluoronitrobenzene and chloronitrobenzene starting materials e.g.2,4-difluoronitrobenzene, 4-fluoro-2-cyano-nitrobenzene,3-nitro-4-chlorobenzene, 2,4,5-trifluoronitrobenzene,2,4,5-trichloronitrobenzene or alternatively from 4-hydroxyphenyl and4-aminophenyl acetic acid starting materials by one skilled in the artof organic synthesis using established organic synthesis procedures.

The 1-position acetic acid moiety common to compounds of Formulas I andII, as the free acid itself or as an ester derivative thereof, isalready present in the case of a 4-hydroxyphenyl acetic acid or4-hydroxyphenyl acetic acid ester starting material. In the case of a4-fluoronitrobenzene starting materials or intermediates, the aceticacid moiety can be introduced by standard nucleophilic aromaticsubstitution of the 4-fluoro group with an unsubstituted malonic ester(eg diethyl malonate) or a malonic ester derivative already bearing anR₁ group (eg. diethyl 2-isobutylmalonate). Introduction of the X—R₃ andY—R₄ groups or intermediate groups that are further elaborated to X—R₃and Y—R₄ can be carried out by substitution or manipulation of suitable3 or 4-position functional groups in appropriate starting materials orintermediates en route to Formulas I and II respectively. In cases whereX or Y is a bond, a 3 or 4-position halogen or triflate group isreplaced with an aryl or heteroaryl group by carbon-carbon bond formingreaction typically a Suzuki coupling reaction. In cases where X or Y isO, S or N, a 3 or 4-position halogen (eg the corresponding 2-fluorogroup of a 2,4-difluoronitrobenzene starting material) substitutionreaction is performed using HO—R₃ or HS—R₃ or H₂N—R₃ and a base (eg NaH,K₂CO₃) in a suitable solvent (eg DMF). Compounds where X or Y is —S(O)—or —S(O₂)— are prepared by oxidation of compounds where X or Y is S.Compounds where X or Y is —S(O)₂N(H)—, —S(O)₂N(R₅)— can be prepared byconversion of a 3 or 4-position nitro group (eg the nitro group of thenitrobenzene starting material) to a sulfonyl chloride via Sandmeyerreaction followed by addition of the corresponding amine. Compoundswhere X or Y is N(H)S(O)₂— or —N(R₅)S(O)₂— can be prepared by reductionof a 3 or 4-position nitro group to the corresponding aniline followedby reaction with the corresponding sulfonylchloride. Compounds where Xor Y is NHC(O)— or —N(R₅)C(O)— can be prepared by reduction of a 3 or4-position nitro group to the corresponding aniline followed by reactionwith the corresponding carboxylic acid chloride. Compounds where X or Yis a —C(O)— can be prepared by addition of an organometallic reagent(e.g., a Grignard reagent or organolithium) to a 3 or 4-position cyanogroup directly or in a 2-step sequence by addition of an organometallicreagent to a 3 or 4-position carboxaldehyde group followed by oxidation.Compounds where X or Y is —C(O)NH— or C(O)N(R₅)—)— can be prepared byaddition of a corresponding amine to a 3 or 4-position carboxylic acidwhich in turn may be prepared by hydrolysis of a 3 or 4-position cyanogroup. Either aromatic nucleophilic substitution of a2-fluoro-1-nitrobenzene intermediate or alkylation of a 3 or4-hydroxybenzene intermediate with the corresponding alkyl bromide ortriflate may be used to prepare compounds of Formulas I and II where theR₄ group is OCH₂CF₃, C2-C4 alkoxy, or cyclopropyloxymethyl. Compoundswherein the R₄ group is an alkyl, aryl or heteroaryl group attached by acarbon-carbon bond may be prepared by a Suzuki coupling reaction. Inthis process an aryl or heteroaryl boronic acid or borate ester isreacted with an intermediate compound having a 3 or 4-position halogenor triflate group. This method results in replacement of the halogen ortriflate group with an aryl or heteroaryl group which is then bonded tothe intermediate at the carbon atom previously bearing the boronic acidor ester group. Compounds wherein the R₄ group is a heteroaryl groupattached by a carbon-nitrogen bond may be prepared by reacting a 3 or4-iodo intermediate with a heteroaromatic heterocycle having an acidicN—H group under Ulman reaction or copper catalyzed reaction conditions.

Compounds of Formulas I and II wherein A=tetrazole may be prepared fromtheir corresponding nitriles A=CN which are available via dehydration ofthe corresponding primary amides A=CONH₂ whose preparation is describedabove. Thus, treatment of the nitrile with an azide, such as sodiumazide or tributylstanyl azide (Bu₃SnN₃) at a temperature of 20-100° C.,optionally with a solvent such as DMF, THF or DMSO.

Compounds of the disclosure of Formula III in which R₁ is R₈ an alkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, oran arylalkyl group, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkylgroup, Y is O, X is a bond, R₃ is Z, R₄ and R₅ are as describedpreviously and thus having general Formula XXIV may be preparedgenerally as depicted in Scheme 1.

Thus, as depicted in Scheme 1 an alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl or arylalkyl R₈group is introduced in the first step by treating ethyl4-benzyloxyphenylacetate one equivalent of a suitable deprotonating basesuch as sodium hydride in an appropriate organic solvent followed by theaddition of the corresponding reactive alkyl bromide R₈Br such asisobutylbromide to yield XX where R₉ is hydrogen. In cases where asecond alkyl or aralkyl group is present this alkylation step isrepeated using R₉Br as an alkylating agent. In cases where a spirocyclicring is formed by R₈ and R₉ (e.g. cyclopropyl) then the appropriatedibromide is used (e.g. dibromoethane in the case of cyclopropyl). Thebenzyl group is then removed under standard catalytic hydrogenationconditions and the resulting phenol is treated with bromine in aceticacid to give the bromophenol intermediate XXI. Nitration of XXI thenyields nitrophenol intermediate XXII which then us subjected to astandard base mediated aliphatic or aromatic nucleophilic substitutionreaction with an alkyl or aryl halide R₄—X to give intermediate XXIIIwhere R₄ is alkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,arylalkyl, heteroarylalkyl, aryl or heteroaryl. This is then followed byintroduction of the Z group by standard reactions. Such reactions areexemplified by the well established Suzuki coupling of a substitutedaryl or heteroaryl boronic acid derivative Z—B(OH)₂ using a suitablepalladium(0) catalyst typically bearing with phosphine ligands (e.g.Pd(PPh₃)₄ or tetrakistriphenylphosphine) in the case where Z is linkedby a carbon-carbon bond and by copper (eg CuI) mediated Ulman typecoupling of a heteroaryl ring bearing an active N—H group where Z is aheteroaryl ring linked by a nitrogen-carbon bond.

After introduction of the Z group, the nitro group is converted to thecorresponding aniline by any number of standard reduction conditions (egSnCl₂ reduction). This is followed by conversion of the resultinganiline to the diazonium salt which is then converted “in situ” eitherdirectly to R₅ either directly in the case where R₅ is F, Cl, Br, CN,OH, C1-C4 alkoxy or SR₆, by using the appropriate copper salt ie CuCl,CuBr, CuCN or nucleophile ie water, alcohol or thiol or in a subsequentstep e.g. oxidation (eg with MCPBA) of the product of thiol couplingwhen R₅ is S(O)₂R₆; e.g. Suzuki coupling of the bromide product when R₅is heteroaryl e.g. treatment of an intermediate sulfonylchlorideobtained via CuCl/SO₂ conditions with an amine HN(R₇)₂, when R₅ isS(O)₂N(R₇)₂, e.g. Burton trifluoromethylation reaction of the iodideproduct (Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014and 1986, 108, 832; Miller, J. A., Coleman, M. C.; Matthews, R. S. J.Org. Chem. 1993, 58, 2637) when R₅ is CF₃ Standard ester hydrolysisyields compounds of Formula XXIV.

Compounds of the disclosure of Formula III in which R₁ is OH, OR₆, SR₆,NHR₇, N(R₇)₂NHC(O)R₆ or NHCO₂R₆; R₂ is H; Y is O, X is a bond, R₃ is Z,R₄ and R₅ are as described previously and thus having general FormulaXXVII may be prepared generally as depicted in Scheme 2. Thus, asdepicted in Scheme 2 bromination of intermediates of general FormulaXXV, prepared according to Scheme 1, e.g. with N-bromosuccinimide (NBS)yields intermediate XXVI. In a subsequent step the Br atom is replacedby a suitable alkoxide, thiolate or masked amine nucleophile (eg azideor N₃). The product of the latter reaction is either directly subjectedto ester hydrolysis or further processed in optional steps (eg byconversion the masked amine to an amino group followed by reductiveamination to give mono or dialkylamine derivatives, and optionallyacylation or carbamoylation of such amine derivatives) and thensubjected to final ester hydrolysis to give compounds of Formula XXVIIin which R₁₀ is OH, OR₆, SR₆, NHR₇, N(R₇)₂NHC(O)R₆ or NHCO₂R₆

Compounds of the disclosure of Formula III and IV in which R₁ is R₈ analkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,heteroarylalkyl, or an arylalkyl group, R₂ is R₉ a hydrogen, alkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, Xand Y are a bond, R₃ and R₄ are respectively Z₁ and Z₂ representingindependently chosen Z groups as defined above and R₅ is as describedpreviously and thus having general Formula XXX may be prepared generallyas depicted in Scheme 3 starting from compounds of general Formula XXIIwhich can be prepared as described in Scheme 1.

Compounds of Formula V in which R₁ is R₈ an alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkylgroup, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is Q═O, S, orSO₂; R₅ is F or Cl; R₃ and Z are as described previously and thus havinggeneral Formula XXXIV may be prepared generally as depicted in Scheme 4.Accordingly, the 4-halo group of 2,4,5-trifluoronitrobenzene or2,4,5-trichloronitrobenzene is selectively displaced by reaction with a2-substituted diethylmalonate R₈YCH(CO₂Et)₂ under basic conditions (egNaH/DMF) followed by hydrolysis and esterification to give intermediateXXXI. Subsequently the 2-halo group undergoes nucleophilic aromaticsubstitution reaction by treatment with a R₃-J-H compound (wherein J isO, S) under basic conditions (eg NaH/DMF) followed by reduction andSandmeyer reaction to give iodide XXXII.

Suzuki coupling then gives intermediates of general formula XXXIII.Introduction of an R₉ group may be conducted using alkylation conditionsdescribed above. Compounds wherein J is SO₂ may be prepared by standardoxidation of intermediates XXXIII wherein J is S. Final products havinggeneral Formula XXXIV are then prepared by standard ester hydrolysis.

Compounds of Formula IV in which R₁ is R₈ an alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkylgroup, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is O; R₅ is Cl;R₃ and Z are as described previously and thus having general FormulaXXXVIII may be prepared generally as depicted in Scheme 5. Accordingly,the 4-fluoro group of 2,4-difluoronitrobenzene is selectively displacedby reaction with a 2-substituted diethylmalonate R₈CH₂(CO₂Et)₂ underbasic conditions (eg NaH/DMF) followed by hydrolysis and esterificationto give intermediate XXXV. Subsequently the 2-halo group undergoesnucleophilic aromatic substitution reaction by treatment with a R₃—O—Hcompound under basic conditions (eg NaH/DMF) followed by reduction andchlorination reaction (eg with N-chlorosuccinimide) to givechloroaniline intermediates of general formula XXXVI. Sandmeyeriodination reaction to followed by Suzuki coupling then givesintermediates of general formula XXXVII. Introduction of an R₉ group maybe conducted using alkylation conditions described above. Final productshaving general Formula XXXVIII are then prepared by standard esterhydrolysis.

Compounds of Formula IV in which R₁ is R₈ an alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkylgroup, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J=O, S; R₅ isNO₂, NH₂, CN, SR₆, SO₂R₆, SO₂N(R₇)₂F, Cl, Br; R₃ and Z are as describedpreviously and thus having general Formula XLII may be preparedgenerally as depicted in Scheme 6. Accordingly, the 2-fluoro group of2,4-difluoronitrobenzene is selectively displaced by reaction with a analcohol or thiol of formula R₃-J-H under basic conditions (eg NaH/DMF).The 4-fluoro group of the resulting product is substituted withdiethylmalonate under basic conditions (eg NaH/DMF) followed byhydrolysis and esterification to give intermediates of Formula XXXIX.Reduction of the nitro group of XXXIX followed by nitration of theresulting aniline give nitroaniline intermediates of Formula XL.Sandmeyer iodination reaction, followed by Suzuki coupling and finallyalkylation reaction to introduce R₈ then gives intermediates of generalFormula XLI. The nitro group of XLI may be optionally reduced via anynumber of standard reduction conditions (eg SnCl₂) to an aniline whichmay in turn optionally be converted to diverse other R₅ groups eitherdirectly or in multistep procedures. Thus, in the case where R₅ is F,Cl, Br, CN, OH, C1-C4 alkoxy or SR₆, diazotization of the aniline isfollowed by direct “in situ” conversion to R₅ using the appropriatecopper salt ie CuCl, CuBr, CuCN or nucleophile ie water, alcohol orthiol. Intermediates where R₅ is S(O)₂R₆ may be prepared by subsequentstep oxidation (eg with MCPBA) of the above products of thiol couplingwherein R₅ is SR₆. Intermediates where R₅ is eg heteroaryl, C2-C4alkynyl or cyclopropyl may be prepared by subsequent Suzuki coupling ofthe above products wherein R₅ is Br or I. Intermediates where R₅ is CF3may be prepared by Burton reaction of the above products wherein R₅ isI. Intermediates where R₅ is S(O)₂N(R₇)₂, may be prepared by subsequentreaction of above direct sulfonylchloride products (obtained viaCuCl/SO₂ conditions) with an amine HN(R₇)₂, Final products havinggeneral Formula XLII are then prepared by optional alkylation reactionto introduce R₉ followed by standard ester hydrolysis.

Compounds of Formula VII in which R₁ is R₈ an alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkylgroup, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X is J=O, S; R₅ isNO₂, NH₂, CN, SR₆, SO₂R₆, SO₂N(R₇)₂F, Cl, Br; R₃ and Z are as describedpreviously and thus having general Formula XLV may be prepared generallyas depicted in Scheme 7. Reduction of the nitro group of XXXIX followedby bromination (eg with NBS) of the resulting aniline and prepared by 1alkylation reaction to introduce R₉ gives bromoaniline intermediates ofFormula XLIII Suzuki coupling reaction substitutes Z groups for the Brgroup to give intermediates of general Formula XLIV. The aniline groupin intermediates of Formula XLIV may in turn optionally be converted todiverse other R₅ groups either directly or in multistep procedures.Thus, in the case where R₅ is F, Cl, Br, CN, OH, C1-C4 alkoxy or SR₆,diazotization of the aniline is followed by direct “in situ” conversionto R₅ using the appropriate copper salt ie CuCl, CuBr, CuCN ornucleophile ie water, alcohol or thiol. Intermediates where R₅ isS(O)₂R₆ may be prepared by subsequent step oxidation (eg with MCPBA) ofthe above products of thiol coupling wherein R₅ is SR₆. Intermediateswhere R₅ is eg heteroaryl, C2-C4 alkynyl or cyclopropyl may be preparedby subsequent Suzuki coupling of the above products wherein R₅ is Br orI. Intermediates where R₅ is CF3 may be prepared by Burton reaction ofthe above products wherein R₅ is I. Intermediates where R₅ isS(O)₂N(R₇)₂, may be prepared by subsequent reaction of above directsulfonylchloride products (obtained via CuCl/SO₂ conditions) with anamine HN(R₇)₂, Final products having general Formula XLII are thenprepared by optional alkylation reaction to introduce R₉ followed bystandard ester hydrolysis.

Compounds of Formula IV in which R₁ is R₈ an alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl, or an arylalkylgroup, R₂ is R₉ a hydrogen, alkyl, cycloalkylalkyl,heterocycloalkylalkyl, alkoxyalkyl, heteroarylalkyl; X—R₃ and R₅ areidentical (J-R3 in Scheme 8) and are either C1-C4 alkoxy or SR₆ groups;and Z is as described previously and thus having general Formula L maybe prepared generally as depicted in Scheme 8. Accordingly, the 2 and6-fluoro groups of 2,4,6-trifluoronitrobenzene are selectively displacedby reaction with a an alcohol or thiol of formula R₃-J-H under basicconditions (eg NaH/DMF). The 4-fluoro group of the resulting product issubstituted with diethylmalonate under basic conditions (eg NaH/DMF)followed by hydrolysis and esterification to give intermediates ofFormula XLVIII. Reduction of the nitro group of followed by Sandmeyeriodination reaction of the resulting aniline gives intermediates ofFormula XLVIII. Suzuki coupling and followed by alkylation reaction tointroduce R₈ then gives intermediates of general Formula XLIX. Finalproducts having general Formula L are then prepared by optionalalkylation reaction to introduce R₉ followed by standard esterhydrolysis.

Enantioselective Methods

Compounds of formulas I-IX may be prepared in an enantioselectively,this can be accomplished via resolution via chiral HPLC(CHIRALPAK-AD H(250×4.6 mm, 5 μm). Mobile phase: Hexane (0.1% TFA):IPA (93:7), Flowrate 0.8 mL/min., Diluent Hexane:IPA (90:10); Column temperature 40° C.)or via asymmetric synthesis. The phenyl acetic acids of formula (XXXV)are converted into the corresponding acid chlorides, via treatment withSOCl₂ or oxalyl chloride with a catalytic amount of DMF. The reaction isperformed in an inert solvent such as CH₂Cl₂, CHCl₃, THF, or toluene ata temperature of 0-80° C. The acid chloride is treated with either (R)-or (S)-4-benzyloxazolidin-2-one to (R isomer depicted-XXXXVI) give theoxazolidinone (XXXVII). The oxazolidinone ( ) is then subjected to abase such as NaHMDs, LiHMDS, KHMDS, BuL¹ or KO^(t)Bu in an inert solventsuch as THF, Me-THF or Et₂O at a temperature of −78 to 0° C. Thesubsequent enolate is then treated with the appropriate electrophile togive the alkylated oxazolidinone (XXXVIII). The chiral auxillary isremoved under conditions such as LiOH/H₂O₂ followed by a reductive workup with a reagent such as sodium bi-sulfite to give the desired productsof formulas (I-IX).

Alternatively the racemic compound of formula (1-IX) may be coupled tothe Evans chiral oxazolidinone via an intermediate such as thecorresponding acid chloride. Upon completion of the coupling, thereaction produces a mixture of diastereoisomers which may be seprated bymethods such as flash chromatography or crystallization to give singlediastereoisomers or enriched mixtures favouring one diastereoisomer overthe other (see scheme 10). The auxillary may be removed as describedpreviously.

Examples of enantiomers include but are not limited to;

-   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic    acid compound-   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic    acid-   (R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (R)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)pentanoic    acid-   (S)-4-methyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)pentanoic    acid-   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (R)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)pentanoic    acid-   (S)-4-methyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)pentanoic    acid-   (R)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)propanoic    acid-   (S)-3-cyclopropyl-2-(6-(2,2,2-trifluoroethoxy)-4′,5-bis(trifluoromethyl)biphenyl-3-yl)propanoic    acid-   (R)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)propanoic    acid-   (S)-3-cyclopropyl-2-(5-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-3-yl)propanoic    acid-   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (R)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic    acid-   (S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoic    acid-   (R)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)propanoic    acid compound    (S)-3-cyclopropyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)propanoic    acid compound-   (R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic    acid-   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic    acid-   (R)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (S)-2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic    acid-   (S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic    acid-   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic    acid-   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic    acid-   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic    acid-   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic    acid-   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (R)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic    acid-   (S)-2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic    acid-   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic    acid-   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-2-cyclopentylacetic    acid-   (R)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic    acid-   (S)-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic    acid-   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic    acid-   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclobutylpropanoic    acid-   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic    acid-   (R)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic    acid-   (S)-2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-4-methylpentanoic    acid-   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (R)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic    acid-   (S)-2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic    acid-   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (R)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (S)-2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-3-cyclopropylpropanoic    acid-   (R)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl)-4-methylpentanoic    acid-   (R)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)pentanoic    acid-   (S)-4-methyl-2-(2-(2,2,2-trifluoroethoxy)-4′,6-bis(trifluoromethyl)biphenyl-4-yl)pentanoic    acid

In a further aspect the compounds of the disclosure are embodied in withdistinct examples listed in Tables below.

TABLE 1 Formula III Ex R1 R2 Y R4 R5 Z 100 CH3 H O CH2CH3 F4-fluorophenyl 101 CH2CH3 H O CH2CH3 F 4-fluorophenyl 102 CH2CF3 H OCH2CH3 F 4-fluorophenyl 103 CH2CH2CH3 H O CH2CH3 F 4-fluorophenyl 104CH2CH(CH3)2 H O CH2CH3 F 4-fluorophenyl 105 cyclopropylmethyl H O CH2CH3F 4-fluorophenyl 106 SCH(CH3)2 H O CH2CH3 F 4-fluorophenyl 107 OCH2CH3 HO CH2CH3 F 4-fluorophenyl 108 (CH2)2 O CH2CH3 F 4-fluorophenyl 109(CH2)4 O CH2CH3 F 4-fluorophenyl 110 CH3 H O CH2CH3 F 4-chlorophenyl 111CH2CH3 H O CH2CH3 F 4-chlorophenyl 112 CH2CF3 H O CH2CH3 F4-chlorophenyl 113 CH2CH2CH3 H O CH2CH3 F 4-chlorophenyl 114 CH2CH(CH3)2H O CH2CH3 F 4-chlorophenyl 115 cyclopropylmethyl H O CH2CH3 F4-chlorophenyl 116 SCH(CH3)2 H O CH2CH3 F 4-chlorophenyl 117 OCH2CH3 H OCH2CH3 F 4-chlorophenyl 118 (CH2)2 O CH2CH3 F 4-chlorophenyl 119 (CH2)4O CH2CH3 F 4-chlorophenyl 120 CH3 H O CH2CH3 F 4-trifluoromethylphenyl121 CH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl 122 CH2CF3 H O CH2CH3 F4-trifluoromethylphenyl 123 CH2CH2CH3 H O CH2CH3 F4-trifluoromethylphenyl 124 CH2CH(CH3)2 H O CH2CH3 F4-trifluoromethylphenyl 125 cyclopropylmethyl H O CH2CH3 F4-trifluoromethylphenyl 126 SCH(CH3)2 H O CH2CH3 F4-trifluoromethylphenyl 127 OCH2CH3 H O CH2CH3 F 4-trifluoromethylphenyl128 (CH2)2 O CH2CH3 F 4-trifluoromethylphenyl 129 (CH2)4 O CH2CH3 F4-trifluoromethylphenyl 130 CH3 H O CH2CH3 F 4-methoxyphenyl 131 CH2CH3H O CH2CH3 F 4-methoxyphenyl 132 CH2CF3 H O CH2CH3 F 4-methoxyphenyl 133CH2CH2CH3 H O CH2CH3 F 4-methoxyphenyl 134 CH2CH(CH3)2 H O CH2CH3 F4-methoxyphenyl 135 cyclopropylmethyl H O CH2CH3 F 4-methoxyphenyl 136SCH(CH3)2 H O CH2CH3 F 4-methoxyphenyl 137 OCH2CH3 H O CH2CH3 F4-methoxyphenyl 138 (CH2)2 O CH2CH3 F 4-methoxyphenyl 139 (CH2)4 OCH2CH3 F 4-methoxyphenyl 140 CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 141CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 142 CH₂CF₃ H O CH₂CH₃ F 3,4dichloro phenyl 143 CH₂CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 144CH₂CH(CH₃)₂ H O CH₂CH₃ F 3,4 dichloro phenyl 145 cyclopropylmethyl H OCH₂CH₃ F 3,4 dichloro phenyl 146 SCH(CH₃)₂ H O CH₂CH₃ F 3,4 dichlorophenyl 147 OCH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 148 (CH₂)₂ O CH₂CH₃F 3,4 dichloro phenyl 149 (CH₂)₄ O CH₂CH₃ F 3,4 dichloro phenyl 150 CH₃H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 151 CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 152 CH₂CF₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 153 CH₂CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 154 CH₂CH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 155 cyclopropylmethyl H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 156 SCH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 157 OCH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 158 (CH₂)₂ O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 159 (CH₂)₄ O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 160 CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 161 CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 162 CH₂CF₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 163 CH₂CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 164 CH₂CH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 165 cyclopropylmethyl H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 166 SCH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 167 OCH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 168 (CH₂)₂ O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 169 (CH₂)₄ O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 170 CH₃ H O CH₂CH₃ F 4-fluorophenyl 171CH₂CH₃ H O CH₂CH₃ F 4-fluorophenyl 172 CH₂CF₃ H O CH₂CH₃ F4-fluorophenyl 173 CH₂CH₂CH₃ H O CH₂CH₃ F 4-fluorophenyl 174 CH₂CH(CH₃)₂H O CH₂CH₃ F 4-fluorophenyl 175 cyclopropylmethyl H O CH₂CH₃ F4-fluorophenyl 176 SCH(CH₃)₂ H O CH₂CH₃ F 4-fluorophenyl 177 OCH₂CH₃ H OCH₂CH₃ F 4-fluorophenyl 178 (CH₂)₂ O CH₂CH₃ F 4-fluorophenyl 179 (CH₂)₄O CH₂CH₃ F 4-fluorophenyl 180 CH₃ H O CH₂CH₃ F 4-chlorophenyl 181 CH₂CH₃H O CH₂CH₃ F 4-chlorophenyl 182 CH₂CF₃ H O CH₂CH₃ F 4-chlorophenyl 183CH₂CH₂CH₃ H O CH₂CH₃ F 4-chlorophenyl 184 CH₂CH(CH₃)₂ H O CH₂CH₃ F4-chlorophenyl 185 cyclopropylmethyl H O CH₂CH₃ F 4-chlorophenyl 186SCH(CH₃)₂ H O CH₂CH₃ F 4-chlorophenyl 187 OCH₂CH₃ H O CH₂CH₃ F4-chlorophenyl 188 (CH₂)₂ O CH₂CH₃ F 4-chlorophenyl 189 (CH₂)₄ O CH₂CH₃F 4-chlorophenyl 190 CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl 191 CH₂CH₃H O CH₂CH₃ F 4-trifluoromethylphenyl 192 CH₂CF₃ H O CH₂CH₃ F4-trifluoromethylphenyl 193 CH₂CH₂CH₃ H O CH₂CH₃ F4-trifluoromethylphenyl 194 CH₂CH(CH₃)₂ H O CH₂CH₃ F4-trifluoromethylphenyl 195 cyclopropylmethyl H O CH₂CH₃ F4-trifluoromethylphenyl 196 SCH(CH₃)₂ H O CH₂CH₃ F4-trifluoromethylphenyl 197 OCH₂CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl198 (CH₂)₂ O CH₂CH₃ F 4-trifluoromethylphenyl 199 (CH₂)₄ O CH₂CH₃ F4-trifluoromethylphenyl 200 CH₃ H O CH₂CH₃ F 4-methoxyphenyl 201 CH₂CH₃H O CH₂CH₃ F 4-methoxyphenyl 202 CH₂CF₃ H O CH₂CH₃ F 4-methoxyphenyl 203CH₂CH₂CH₃ H O CH₂CH₃ F 4-methoxyphenyl 204 CH₂CH(CH₃)₂ H O CH₂CH₃ F4-methoxyphenyl 205 cyclopropylmethyl H O CH₂CH₃ F 4-methoxyphenyl 206SCH(CH₃)₂ H O CH₂CH₃ F 4-methoxyphenyl 207 OCH₂CH₃ H O CH₂CH₃ F4-methoxyphenyl 208 (CH₂)₂ O CH₂CH₃ F 4-methoxyphenyl 209 (CH₂)₄ OCH₂CH₃ F 4-methoxyphenyl 210 CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 211CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 212 CH₂CF₃ H O CH₂CH₃ F 3,4dichloro phenyl 213 CH₂CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 214CH₂CH(CH₃)₂ H O CH₂CH₃ F 3,4 dichloro phenyl 215 cyclopropylmethyl H OCH₂CH₃ F 3,4 dichloro phenyl 216 SCH(CH₃)₂ H O CH₂CH₃ F 3,4 dichlorophenyl 217 OCH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 218 (CH₂)₂ O CH₂CH₃F 3,4 dichloro phenyl 219 (CH₂)₄ O CH₂CH₃ F 3,4 dichloro phenyl 220 CH₃H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 221 CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 222 CH₂CF₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 223 CH₂CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 224 CH₂CH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 225 cyclopropylmethyl H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 226 SCH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 227 OCH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 228 (CH₂)₂ O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 229 (CH₂)₄ O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 230 CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 231 CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 232 CH₂CF₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 233 CH₂CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 234 CH₂CH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 235 cyclopropylmethyl H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 236 SCH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 237 OCH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 238 (CH₂)₂ O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 239 (CH₂)₄ O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 240 CH₃ H O CH₂-c-Pr F 4-fluorophenyl 241CH₂CH₃ H O CH₂-c-Pr F 4-fluorophenyl 242 CH₂CF₃ H O CH₂-c-Pr F4-fluorophenyl 243 CH₂CH₂CH₃ H O CH₂-c-Pr F 4-fluorophenyl 244CH₂CH(CH₃)₂ H O CH₂-c-Pr F 4-fluorophenyl 245 cyclopropylmethyl H OCH₂-c-Pr F 4-fluorophenyl 246 SCH(CH₃)₂ H O CH₂-c-Pr F 4-fluorophenyl247 OCH₂CH₃ H O CH₂-c-Pr F 4-fluorophenyl 248 (CH₂)₂ O CH₂-c-Pr F4-fluorophenyl 249 (CH₂)₄ O CH₂-c-Pr F 4-fluorophenyl 250 CH₃ H OCH₂-c-Pr F 4-chlorophenyl 251 CH₂CH₃ H O CH₂-c-Pr F 4-chlorophenyl 252CH₂CF₃ H O CH₂-c-Pr F 4-chlorophenyl 253 CH₂CH₂CH₃ H O CH₂-c-Pr F4-chlorophenyl 254 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 4-chlorophenyl 255cyclopropylmethyl H O CH₂-c-Pr F 4-chlorophenyl 256 SCH(CH₃)₂ H OCH₂-c-Pr F 4-chlorophenyl 257 OCH₂CH₃ H O CH₂-c-Pr F 4-chlorophenyl 258(CH₂)₂ O CH₂-c-Pr F 4-chlorophenyl 259 (CH₂)₄ O CH₂-c-Pr F4-chlorophenyl 260 CH₃ H O CH₂-c-Pr F 4-trifluoromethylphenyl 261 CH₂CH₃H O CH₂-c-Pr F 4-trifluoromethylphenyl 262 CH₂CF₃ H O CH₂-c-Pr F4-trifluoromethylphenyl 263 CH₂CH₂CH₃ H O CH₂-c-Pr F4-trifluoromethylphenyl 264 CH₂CH(CH₃)₂ H O CH₂-c-Pr F4-trifluoromethylphenyl 265 cyclopropylmethyl H O CH₂-c-Pr F4-trifluoromethylphenyl 266 SCH(CH₃)₂ H O CH₂-c-Pr F4-trifluoromethylphenyl 267 OCH₂CH₃ H O CH₂-c-Pr F4-trifluoromethylphenyl 268 (CH₂)₂ O CH₂-c-Pr F 4-trifluoromethylphenyl269 (CH₂)₄ O CH₂-c-Pr F 4-trifluoromethylphenyl 270 CH₃ H O CH₂-c-Pr F4-methoxyphenyl 271 CH₂CH₃ H O CH₂-c-Pr F 4-methoxyphenyl 272 CH₂CF₃ H OCH₂-c-Pr F 4-methoxyphenyl 273 CH₂CH₂CH₃ H O CH₂-c-Pr F 4-methoxyphenyl274 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 4-methoxyphenyl 275 cyclopropylmethyl H OCH₂-c-Pr F 4-methoxyphenyl 276 SCH(CH₃)₂ H O CH₂-c-Pr F 4-methoxyphenyl277 OCH₂CH₃ H O CH₂-c-Pr F 4-methoxyphenyl 278 (CH₂)₂ O CH₂-c-Pr F4-methoxyphenyl 279 (CH₂)₄ O CH₂-c-Pr F 4-methoxyphenyl 280 CH₃ H OCH₂-c-Pr F 3,4 dichloro phenyl 281 CH₂CH₃ H O CH₂-c-Pr F 3,4 dichlorophenyl 282 CH₂CF₃ H O CH₂-c-Pr F 3,4 dichloro phenyl 283 CH₂CH₂CH₃ H OCH₂-c-Pr F 3,4 dichloro phenyl 284 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 3,4dichloro phenyl 285 cyclopropylmethyl H O CH₂-c-Pr F 3,4 dichloro phenyl286 SCH(CH₃)₂ H O CH₂-c-Pr F 3,4 dichloro phenyl 287 OCH₂CH₃ H OCH₂-c-Pr F 3,4 dichloro phenyl 288 (CH₂)₂ O CH₂-c-Pr F 3,4 dichlorophenyl 289 (CH₂)₄ O CH₂-c-Pr F 3,4 dichloro phenyl 290 CH₃ H O CH₂-c-PrF 5-benzo[c][1,2,5]oxadiazolyl 291 CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 292 CH₂CF₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 293 CH₂CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 294 CH₂CH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 295 cyclopropylmethyl H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 296 SCH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 297 OCH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 298 (CH₂)₂ O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 299 (CH₂)₄ O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 300 CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 301 CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 302 CH₂CF₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 303 CH₂CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 304 CH₂CH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 305 cyclopropylmethyl H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 306 SCH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 307 OCH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 308 (CH₂)₂ O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 309 (CH₂)₄ O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 310 CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 311CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 312 CH₂CF₃ H O CH₂CH₃ Cl4-fluorophenyl 313 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 314CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 315 cyclopropylmethyl H OCH₂CH₃ Cl 4-fluorophenyl 316 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 317OCH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 318 (CH₂)₂ O CH₂CH₃ Cl4-fluorophenyl 319 (CH₂)₄ O CH₂CH₃ Cl 4-fluorophenyl 320 CH₃ H O CH₂CH₃Cl 4-chlorophenyl 321 CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 322 CH₂CF₃ H OCH₂CH₃ Cl 4-chlorophenyl 323 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 324CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 325 cyclopropylmethyl H OCH₂CH₃ Cl 4-chlorophenyl 326 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 327OCH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 328 (CH₂)₂ O CH₂CH₃ Cl4-chlorophenyl 329 (CH₂)₄ O CH₂CH₃ Cl 4-chlorophenyl 330 CH₃ H O CH₂CH₃Cl 4-trifluoromethylphenyl 331 CH₂CH₃ H O CH₂CH₃ Cl4-trifluoromethylphenyl 332 CH₂CF₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl333 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 334 CH₂CH(CH₃)₂ H OCH₂CH₃ Cl 4-trifluoromethylphenyl 335 cyclopropylmethyl H O CH₂CH₃ Cl4-trifluoromethylphenyl 336 SCH(CH₃)₂ H O CH₂CH₃ Cl4-trifluoromethylphenyl 337 OCH₂CH₃ H O CH₂CH₃ Cl4-trifluoromethylphenyl 338 (CH₂)₂ O CH₂CH₃ Cl 4-trifluoromethylphenyl339 (CH₂)₄ O CH₂CH₃ Cl 4-trifluoromethylphenyl 340 CH₃ H O CH₂CH₃ Cl4-methoxyphenyl 341 CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 342 CH₂CF₃ H OCH₂CH₃ Cl 4-methoxyphenyl 343 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl344 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl 345 cyclopropylmethyl H OCH₂CH₃ Cl 4-methoxyphenyl 346 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl347 OCH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 348 (CH₂)₂ O CH₂CH₃ Cl4-methoxyphenyl 349 (CH₂)₄ O CH₂CH₃ Cl 4-methoxyphenyl 350 CH₃ H OCH₂CH₃ Cl 3,4 dichloro phenyl 351 CH₂CH₃ H O CH₂CH₃ Cl 3,4 dichlorophenyl 352 CH₂CF₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 353 CH₂CH₂CH₃ H OCH₂CH₃ Cl 3,4 dichloro phenyl 354 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichlorophenyl 355 cyclopropylmethyl H O CH₂CH₃ Cl 3,4 dichloro phenyl 356SCH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichloro phenyl 357 OCH₂CH₃ H O CH₂CH₃ Cl3,4 dichloro phenyl 358 (CH₂)₂ O CH₂CH₃ Cl 3,4 dichloro phenyl 359(CH₂)₄ O CH₂CH₃ Cl 3,4 dichloro phenyl 360 CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 361 CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 362 CH₂CF₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 363 CH₂CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 364 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 365 cyclopropylmethyl H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 366 SCH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 367 OCH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 368 (CH₂)₂ O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 369 (CH₂)₄ O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 370 CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 371 CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 372 CH₂CF₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 373 CH₂CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 374 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 375 cyclopropylmethyl H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 376 SCH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 377 OCH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 378 (CH₂)₂ O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 379 (CH₂)₄ O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 380 CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 381CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 382 CH₂CF₃ H O CH₂CF₃ Cl4-fluorophenyl 383 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 384CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 385 cyclopropylmethyl H OCH₂CF₃ Cl 4-fluorophenyl 386 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 387OCH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 388 (CH₂)₂ O CH₂CF₃ Cl4-fluorophenyl 389 (CH₂)₄ O CH₂CF₃ Cl 4-fluorophenyl 400 CH₃ H O CH₂CF₃Cl 4-chlorophenyl 401 CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 402 CH₂CF₃ H OCH₂CF₃ Cl 4-chlorophenyl 403 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 404CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 405 cyclopropylmethyl H OCH₂CF₃ Cl 4-chlorophenyl 406 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 407OCH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 408 (CH₂)₂ O CH₂CF₃ Cl4-chlorophenyl 409 (CH₂)₄ O CH₂CF₃ Cl 4-chlorophenyl 410 CH₃ H O CH₂CF₃Cl 4-trifluoromethylphenyl 411 CH₂CH₃ H O CH₂CF₃ Cl4-trifluoromethylphenyl 412 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl413 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 414 CH₂CH(CH₃)₂ H OCH₂CF₃ Cl 4-trifluoromethylphenyl 415 cyclopropylmethyl H O CH₂CF₃ Cl4-trifluoromethylphenyl 416 SCH(CH₃)₂ H O CH₂CF₃ Cl4-trifluoromethylphenyl 417 OCH₂CH₃ H O CH₂CF₃ Cl4-trifluoromethylphenyl 418 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoromethylphenyl419 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoromethylphenyl 420 CH₃ H O CH₂CF₃ Cl4-methoxyphenyl 421 CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 422 CH₂CF₃ H OCH₂CF₃ Cl 4-methoxyphenyl 423 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl424 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl 425 cyclopropylmethyl H OCH₂CF₃ Cl 4-methoxyphenyl 426 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl427 OCH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 428 (CH₂)₂ O CH₂CF₃ Cl4-methoxyphenyl 429 (CH₂)₄ O CH₂CF₃ Cl 4-methoxyphenyl 430 CH₃ H OCH₂CF₃ Cl 3,4 dichloro phenyl 431 CH₂CH₃ H O CH₂CF₃ Cl 3,4 dichlorophenyl 432 CH₂CF₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 433 CH₂CH₂CH₃ H OCH₂CF₃ Cl 3,4 dichloro phenyl 434 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichlorophenyl 435 cyclopropylmethyl H O CH₂CF₃ Cl 3,4 dichloro phenyl 436SCH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichloro phenyl 437 OCH₂CH₃ H O CH₂CF₃ Cl3,4 dichloro phenyl 438 (CH₂)₂ O CH₂CF₃ Cl 3,4 dichloro phenyl 439(CH₂)₄ O CH₂CF₃ Cl 3,4 dichloro phenyl 440 CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 441 CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 442 CH₂CF₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 443 CH₂CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 444 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 445 cyclopropylmethyl H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 446 SCH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 447 OCH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 448 (CH₂)₂ O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 449 (CH₂)₄ O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 450 CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 451 CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 452 CH₂CF₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 453 CH₂CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 454 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 455 cyclopropylmethyl H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 456 SCH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 457 OCH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 458 (CH₂)₂ O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 459 (CH₂)₄ O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 460 CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 461CH₂CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 462 CH₂CF₃ H O CH₂-c-Pr Cl4-fluorophenyl 463 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 464CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-fluorophenyl 465 cyclopropylmethyl H OCH₂-c-Pr Cl 4-fluorophenyl 466 SCH(CH₃)₂ H O CH₂-c-Pr Cl 4-fluorophenyl467 OCH₂CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 468 (CH₂)₂ O CH₂-c-Pr Cl4-fluorophenyl 469 (CH₂)₄ O CH₂-c-Pr Cl 4-fluorophenyl 470 CH₃ H OCH₂-c-Pr Cl 4-chlorophenyl 471 CH₂CH₃ H O CH₂-c-Pr Cl 4-chlorophenyl 472CH₂CF₃ H O CH₂-c-Pr Cl 4-chlorophenyl 473 CH₂CH₂CH₃ H O CH₂-c-Pr Cl4-chlorophenyl 474 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-chlorophenyl 475cyclopropylmethyl H O CH₂-c-Pr Cl 4-chlorophenyl 476 SCH(CH₃)₂ H OCH₂-c-Pr Cl 4-chlorophenyl 477 OCH₂CH₃ H O CH₂-c-Pr Cl 4-chlorophenyl478 (CH₂)₂ O CH₂-c-Pr Cl 4-chlorophenyl 479 (CH₂)₄ O CH₂-c-Pr Cl4-chlorophenyl 480 CH₃ H O CH₂-c-Pr Cl 4-trifluoromethylphenyl 481CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoromethylphenyl 482 CH₂CF₃ H O CH₂-c-PrCl 4-trifluoromethylphenyl 483 CH₂CH₂CH₃ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 484 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 485 cyclopropylmethyl H O CH₂-c-Pr Cl4-trifluoromethylphenyl 486 SCH(CH₃)₂ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 487 OCH₂CH₃ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 488 (CH₂)₂ O CH₂-c-Pr Cl 4-trifluoromethylphenyl489 (CH₂)₄ O CH₂-c-Pr Cl 4-trifluoromethylphenyl 490 CH₃ H O CH₂-c-Pr Cl4-methoxyphenyl 491 CH₂CH₃ H O CH₂-c-Pr Cl 4-methoxyphenyl 492 CH₂CF₃ HO CH₂-c-Pr Cl 4-methoxyphenyl 493 CH₂CH₂CH₃ H O CH₂-c-Pr Cl4-methoxyphenyl 494 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-methoxyphenyl 495cyclopropylmethyl H O CH₂-c-Pr Cl 4-methoxyphenyl 496 SCH(CH₃)₂ H OCH₂-c-Pr Cl 4-methoxyphenyl 497 OCH₂CH₃ H O CH₂-c-Pr Cl 4-methoxyphenyl498 (CH₂)₂ O CH₂-c-Pr Cl 4-methoxyphenyl 499 (CH₂)₄ O CH₂-c-Pr Cl4-methoxyphenyl 500 CH₃ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 501 CH₂CH₃ HO CH₂-c-Pr Cl 3,4 dichloro phenyl 502 CH₂CF₃ H O CH₂-c-Pr Cl 3,4dichloro phenyl 503 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 504CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 505 cyclopropylmethyl HO CH₂-c-Pr Cl 3,4 dichloro phenyl 506 SCH(CH₃)₂ H O CH₂-c-Pr Cl 3,4dichloro phenyl 507 OCH₂CH₃ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 508(CH₂)₂ O CH₂-c-Pr Cl 3,4 dichloro phenyl 509 (CH₂)₄ O CH₂-c-Pr Cl 3,4dichloro phenyl 510 CH₃ H O CH₂-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 511CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 512 CH₂CF₃ H OCH₂-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 513 CH₂CH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 514 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 515 cyclopropylmethyl H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 516 SCH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 517 OCH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 518 (CH₂)₂ O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 519 (CH₂)₄ O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 520 CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 521 CH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 522 CH₂CF₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 523 CH₂CH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 524 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 525 cyclopropylmethyl H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 526 SCH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 527 OCH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 528 (CH₂)₂ O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 529 (CH₂)₄ O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 530 CH₃ H O CH₂-c-Pr NO24-trifluoromethylphenyl 531 CH₂CH₃ H O CH₂-c-Pr NO24-trifluoromethylphenyl 532 CH₂CF₃ H O CH₂-c-Pr NO24-trifluoromethylphenyl 533 CH₂CH₂CH₃ H O CH₂-c-Pr NO24-trifluoromethylphenyl 534 CH₂CH(CH₃)₂ H O CH₂-c-Pr NO24-trifluoromethylphenyl 535 cyclopropylmethyl H O CH₂-c-Pr NO24-trifluoromethylphenyl 536 SCH(CH₃)₂ H O CH₂-c-Pr NO24-trifluoromethylphenyl 537 OCH₂CH₃ H O CH₂-c-Pr NO24-trifluoromethylphenyl 538 (CH₂)₂ O CH₂-c-Pr NO24-trifluoromethylphenyl 539 (CH₂)₄ O CH₂-c-Pr NO24-trifluoromethylphenyl 540 CH₃ H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 541 CH₂CH₃ H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 542 CH₂CF₃ H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 543 CH₂CH₂CH₃ H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 544 CH₂CH(CH₃)₂ H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 545 cyclopropylmethyl H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 546 SCH(CH₃)₂ H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 547 OCH₂CH₃ H O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 548 (CH₂)₂ O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 549 (CH₂)₄ O CH₂-c-Pr NO25-benzo[c][1,2,5]oxadiazolyl 550 CH₃ H O CH₂-c-Pr NH24-trifluoromethylphenyl 551 CH₂CH₃ H O CH₂-c-Pr NH24-trifluoromethylphenyl 552 CH₂CF₃ H O CH₂-c-Pr NH24-trifluoromethylphenyl 553 CH₂CH₂CH₃ H O CH₂-c-Pr NH24-trifluoromethylphenyl 554 CH₂CH(CH₃)₂ H O CH₂-c-Pr NH24-trifluoromethylphenyl 555 cyclopropylmethyl H O CH₂-c-Pr NH24-trifluoromethylphenyl 556 SCH(CH₃)₂ H O CH₂-c-Pr NH24-trifluoromethylphenyl 557 OCH₂CH₃ H O CH₂-c-Pr NH24-trifluoromethylphenyl 558 (CH₂)₂ O CH₂-c-Pr NH24-trifluoromethylphenyl 559 (CH₂)₄ O CH₂-c-Pr NH24-trifluoromethylphenyl

TABLE 2 Formula V EX R1 R2 X R3 R5 Z 560 CH₃ H O CH₂CH₃ F 4-fluorophenyl561 CH₂CH₃ H O CH₂CH₃ F 4-fluorophenyl 562 CH₂CF₃ H O CH₂CH₃ F4-fluorophenyl 563 CH₂CH₂CH₃ H O CH₂CH₃ F 4-fluorophenyl 564 CH₂CH(CH₃)₂H O CH₂CH₃ F 4-fluorophenyl 565 cyclopropylmethyl H O CH₂CH₃ F4-fluorophenyl 566 SCH(CH₃)₂ H O CH₂CH₃ F 4-fluorophenyl 567 OCH₂CH₃ H OCH₂CH₃ F 4-fluorophenyl 568 (CH₂)₂ O CH₂CH₃ F 4-fluorophenyl 569 (CH₂)₄O CH₂CH₃ F 4-fluorophenyl 570 CH₃ H O CH₂CH₃ F 4-chlorophenyl 571 CH₂CH₃H O CH₂CH₃ F 4-chlorophenyl 572 CH₂CF₃ H O CH₂CH₃ F 4-chlorophenyl 573CH₂CH₂CH₃ H O CH₂CH₃ F 4-chlorophenyl 574 CH₂CH(CH₃)₂ H O CH₂CH₃ F4-chlorophenyl 575 cyclopropylmethyl H O CH₂CH₃ F 4-chlorophenyl 576SCH(CH₃)₂ H O CH₂CH₃ F 4-chlorophenyl 577 OCH₂CH₃ H O CH₂CH₃ F4-chlorophenyl 578 (CH₂)₂ O CH₂CH₃ F 4-chlorophenyl 579 (CH₂)₄ O CH₂CH₃F 4-chlorophenyl 580 CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl 581 CH₂CH₃H O CH₂CH₃ F 4-trifluoromethylphenyl 582 CH₂CF₃ H O CH₂CH₃ F4-trifluoromethylphenyl 583 CH₂CH₂CH₃ H O CH₂CH₃ F4-trifluoromethylphenyl 584 CH₂CH(CH₃)₂ H O CH₂CH₃ F4-trifluoromethylphenyl 585 cyclopropylmethyl H O CH₂CH₃ F4-trifluoromethylphenyl 586 SCH(CH₃)₂ H O CH₂CH₃ F4-trifluoromethylphenyl 587 OCH₂CH₃ H O CH₂CH₃ F 4-trifluoromethylphenyl588 (CH₂)₂ O CH₂CH₃ F 4-trifluoromethylphenyl 589 (CH₂)₄ O CH₂CH₃ F4-trifluoromethylphenyl 590 CH₃ H O CH₂CH₃ F 4-methoxyphenyl 591 CH₂CH₃H O CH₂CH₃ F 4-methoxyphenyl 592 CH₂CF₃ H O CH₂CH₃ F 4-methoxyphenyl 593CH₂CH₂CH₃ H O CH₂CH₃ F 4-methoxyphenyl 594 CH₂CH(CH₃)₂ H O CH₂CH₃ F4-methoxyphenyl 595 cyclopropylmethyl H O CH₂CH₃ F 4-methoxyphenyl 596SCH(CH₃)₂ H O CH₂CH₃ F 4-methoxyphenyl 597 OCH₂CH₃ H O CH₂CH₃ F4-methoxyphenyl 598 (CH₂)₂ O CH₂CH₃ F 4-methoxyphenyl 599 (CH₂)₄ OCH₂CH₃ F 4-methoxyphenyl 600 CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 601CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 602 CH₂CF₃ H O CH₂CH₃ F 3,4dichloro phenyl 603 CH₂CH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 604CH₂CH(CH₃)₂ H O CH₂CH₃ F 3,4 dichloro phenyl 605 cyclopropylmethyl H OCH₂CH₃ F 3,4 dichloro phenyl 606 SCH(CH₃)₂ H O CH₂CH₃ F 3,4 dichlorophenyl 607 OCH₂CH₃ H O CH₂CH₃ F 3,4 dichloro phenyl 608 (CH₂)₂ O CH₂CH₃F 3,4 dichloro phenyl 609 (CH₂)₄ O CH₂CH₃ F 3,4 dichloro phenyl 610 CH₃H O CH₂CH₃ F 5-benzo[c][1,2,5]oxadiazolyl 611 CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 612 CH₂CF₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 613 CH₂CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 614 CH₂CH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 615 cyclopropylmethyl H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 616 SCH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 617 OCH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 618 (CH₂)₂ O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 619 (CH₂)₄ O CH₂CH₃ F5-benzo[c][1,2,5]oxadiazolyl 620 CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 621 CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 622 CH₂CF₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 623 CH₂CH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 624 CH₂CH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 625 cyclopropylmethyl H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 626 SCH(CH₃)₂ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 627 OCH₂CH₃ H O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 628 (CH₂)₂ O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 629 (CH₂)₄ O CH₂CH₃ F5-benzo[c][1,2,5]thiadiazolyl 630 CH₃ H O CH₂CF₃ F 4-fluorophenyl 631CH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 632 CH₂CF₃ H O CH₂CF₃ F4-fluorophenyl 633 CH₂CH₂CH₃ H O CH₂CF₃ F 4-fluorophenyl 634 CH₂CH(CH₃)₂H O CH₂CF₃ F 4-fluorophenyl 635 cyclopropylmethyl H O CH₂CF₃ F4-fluorophenyl 636 SCH(CH₃)₂ H O CH₂CF₃ F 4-fluorophenyl 637 OCH₂CH₃ H OCH₂CF₃ F 4-fluorophenyl 638 (CH₂)₂ O CH₂CF₃ F 4-fluorophenyl 639 (CH₂)₄O CH₂CF₃ F 4-fluorophenyl 640 CH₃ H O CH₂CF₃ F 4-chlorophenyl 641 CH₂CH₃H O CH₂CF₃ F 4-chlorophenyl 642 CH₂CF₃ H O CH₂CF₃ F 4-chlorophenyl 643CH₂CH₂CH₃ H O CH₂CF₃ F 4-chlorophenyl 644 CH₂CH(CH₃)₂ H O CH₂CF₃ F4-chlorophenyl 645 cyclopropylmethyl H O CH₂CF₃ F 4-chlorophenyl 646SCH(CH₃)₂ H O CH₂CF₃ F 4-chlorophenyl 647 OCH₂CH₃ H O CH₂CF₃ F4-chlorophenyl 648 (CH₂)₂ O CH₂CF₃ F 4-chlorophenyl 649 (CH₂)₄ O CH₂CF₃F 4-chlorophenyl 650 CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl 651 CH₂CH₃H O CH₂CF₃ F 4-trifluoromethylphenyl 652 CH₂CF₃ H O CH₂CF₃ F4-trifluoromethylphenyl 653 CH₂CH₂CH₃ H O CH₂CF₃ F4-trifluoromethylphenyl 654 CH₂CH(CH₃)₂ H O CH₂CF₃ F4-trifluoromethylphenyl 655 cyclopropylmethyl H O CH₂CF₃ F4-trifluoromethylphenyl 656 SCH(CH₃)₂ H O CH₂CF₃ F4-trifluoromethylphenyl 657 OCH₂CH₃ H O CH₂CF₃ F 4-trifluoromethylphenyl658 (CH₂)₂ O CH₂CF₃ F 4-trifluoromethylphenyl 659 (CH₂)₄ O CH₂CF₃ F4-trifluoromethylphenyl 660 CH₃ H O CH₂CF₃ F 4-methoxyphenyl 661 CH₂CH₃H O CH₂CF₃ F 4-methoxyphenyl 662 CH₂CF₃ H O CH₂CF₃ F 4-methoxyphenyl 663CH₂CH₂CH₃ H O CH₂CF₃ F 4-methoxyphenyl 664 CH₂CH(CH₃)₂ H O CH₂CF₃ F4-methoxyphenyl 665 cyclopropylmethyl H O CH₂CF₃ F 4-methoxyphenyl 666SCH(CH₃)₂ H O CH₂CF₃ F 4-methoxyphenyl 667 OCH₂CH₃ H O CH₂CF₃ F4-methoxyphenyl 668 (CH₂)₂ O CH₂CF₃ F 4-methoxyphenyl 669 (CH₂)₄ OCH₂CF₃ F 4-methoxyphenyl 670 CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 671CH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 672 CH₂CF₃ H O CH₂CF₃ F 3,4dichloro phenyl 673 CH₂CH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 674CH₂CH(CH₃)₂ H O CH₂CF₃ F 3,4 dichloro phenyl 675 cyclopropylmethyl H OCH₂CF₃ F 3,4 dichloro phenyl 676 SCH(CH₃)₂ H O CH₂CF₃ F 3,4 dichlorophenyl 677 OCH₂CH₃ H O CH₂CF₃ F 3,4 dichloro phenyl 678 (CH₂)₂ O CH₂CF₃F 3,4 dichloro phenyl 679 (CH₂)₄ O CH₂CF₃ F 3,4 dichloro phenyl 680 CH₃H O CH₂CF₃ F 5-benzo[c][1,2,5]oxadiazolyl 681 CH₂CH₃ H O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 682 CH₂CF₃ H O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 683 CH₂CH₂CH₃ H O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 684 CH₂CH(CH₃)₂ H O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 685 cyclopropylmethyl H O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 686 SCH(CH₃)₂ H O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 687 OCH₂CH₃ H O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 688 (CH₂)₂ O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 689 (CH₂)₄ O CH₂CF₃ F5-benzo[c][1,2,5]oxadiazolyl 690 CH₃ H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 691 CH₂CH₃ H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 692 CH₂CF₃ H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 693 CH₂CH₂CH₃ H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 694 CH₂CH(CH₃)₂ H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 695 cyclopropylmethyl H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 696 SCH(CH₃)₂ H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 697 OCH₂CH₃ H O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 698 (CH₂)₂ O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 699 (CH₂)₄ O CH₂CF₃ F5-benzo[c][1,2,5]thiadiazolyl 700 CH₃ H O CH₂-c-Pr F 4-fluorophenyl 701CH₂CH₃ H O CH₂-c-Pr F 4-fluorophenyl 702 CH₂CF₃ H O CH₂-c-Pr F4-fluorophenyl 703 CH₂CH₂CH₃ H O CH₂-c-Pr F 4-fluorophenyl 704CH₂CH(CH₃)₂ H O CH₂-c-Pr F 4-fluorophenyl 705 cyclopropylmethyl H OCH₂-c-Pr F 4-fluorophenyl 706 SCH(CH₃)₂ H O CH₂-c-Pr F 4-fluorophenyl707 OCH₂CH₃ H O CH₂-c-Pr F 4-fluorophenyl 708 (CH₂)₂ O CH₂-c-Pr F4-fluorophenyl 709 (CH₂)₄ O CH₂-c-Pr F 4-fluorophenyl 710 CH₃ H OCH₂-c-Pr F 4-chlorophenyl 711 CH₂CH₃ H O CH₂-c-Pr F 4-chlorophenyl 712CH₂CF₃ H O CH₂-c-Pr F 4-chlorophenyl 713 CH₂CH₂CH₃ H O CH₂-c-Pr F4-chlorophenyl 714 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 4-chlorophenyl 715cyclopropylmethyl H O CH₂-c-Pr F 4-chlorophenyl 716 SCH(CH₃)₂ H OCH₂-c-Pr F 4-chlorophenyl 717 OCH₂CH₃ H O CH₂-c-Pr F 4-chlorophenyl 718(CH₂)₂ O CH₂-c-Pr F 4-chlorophenyl 719 (CH₂)₄ O CH₂-c-Pr F4-chlorophenyl 720 CH₃ H O CH₂-c-Pr F 4-trifluoromethylphenyl 721 CH₂CH₃H O CH₂-c-Pr F 4-trifluoromethylphenyl 722 CH₂CF₃ H O CH₂-c-Pr F4-trifluoromethylphenyl 723 CH₂CH₂CH₃ H O CH₂-c-Pr F4-trifluoromethylphenyl 724 CH₂CH(CH₃)₂ H O CH₂-c-Pr F4-trifluoromethylphenyl 725 cyclopropylmethyl H O CH₂-c-Pr F4-trifluoromethylphenyl 726 SCH(CH₃)₂ H O CH₂-c-Pr F4-trifluoromethylphenyl 727 OCH₂CH₃ H O CH₂-c-Pr F4-trifluoromethylphenyl 728 (CH₂)₂ O CH₂-c-Pr F 4-trifluoromethylphenyl729 (CH₂)₄ O CH₂-c-Pr F 4-trifluoromethylphenyl 730 CH₃ H O CH₂-c-Pr F4-methoxyphenyl 731 CH₂CH₃ H O CH₂-c-Pr F 4-methoxyphenyl 732 CH₂CF₃ H OCH₂-c-Pr F 4-methoxyphenyl 733 CH₂CH₂CH₃ H O CH₂-c-Pr F 4-methoxyphenyl734 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 4-methoxyphenyl 735 cyclopropylmethyl H OCH₂-c-Pr F 4-methoxyphenyl 736 SCH(CH₃)₂ H O CH₂-c-Pr F 4-methoxyphenyl737 OCH₂CH₃ H O CH₂-c-Pr F 4-methoxyphenyl 738 (CH₂)₂ O CH₂-c-Pr F4-methoxyphenyl 739 (CH₂)₄ O CH₂-c-Pr F 4-methoxyphenyl 740 CH₃ H OCH₂-c-Pr F 3,4 dichloro phenyl 741 CH₂CH₃ H O CH₂-c-Pr F 3,4 dichlorophenyl 742 CH₂CF₃ H O CH₂-c-Pr F 3,4 dichloro phenyl 743 CH₂CH₂CH₃ H OCH₂-c-Pr F 3,4 dichloro phenyl 744 CH₂CH(CH₃)₂ H O CH₂-c-Pr F 3,4dichloro phenyl 745 cyclopropylmethyl H O CH₂-c-Pr F 3,4 dichloro phenyl746 SCH(CH₃)₂ H O CH₂-c-Pr F 3,4 dichloro phenyl 747 OCH₂CH₃ H OCH₂-c-Pr F 3,4 dichloro phenyl 748 (CH₂)₂ O CH₂-c-Pr F 3,4 dichlorophenyl 749 (CH₂)₄ O CH₂-c-Pr F 3,4 dichloro phenyl 750 CH₃ H O CH₂-c-PrF 5-benzo[c][1,2,5]oxadiazolyl 751 CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 752 CH₂CF₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 753 CH₂CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 754 CH₂CH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 755 cyclopropylmethyl H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 756 SCH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 757 OCH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 758 (CH₂)₂ O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 759 (CH₂)₄ O CH₂-c-Pr F5-benzo[c][1,2,5]oxadiazolyl 760 CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 761 CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 762 CH₂CF₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 763 CH₂CH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 764 CH₂CH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 765 cyclopropylmethyl H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 766 SCH(CH₃)₂ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 767 OCH₂CH₃ H O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 768 (CH₂)₂ O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 769 (CH₂)₄ O CH₂-c-Pr F5-benzo[c][1,2,5]thiadiazolyl 770 CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 771CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 772 CH₂CF₃ H O CH₂CH₃ Cl4-fluorophenyl 773 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 774CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 775 cyclopropylmethyl H OCH₂CH₃ Cl 4-fluorophenyl 776 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-fluorophenyl 777OCH₂CH₃ H O CH₂CH₃ Cl 4-fluorophenyl 778 (CH₂)₂ O CH₂CH₃ Cl4-fluorophenyl 779 (CH₂)₄ O CH₂CH₃ Cl 4-fluorophenyl 780 CH₃ H O CH₂CH₃Cl 4-chlorophenyl 781 CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 782 CH₂CF₃ H OCH₂CH₃ Cl 4-chlorophenyl 783 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 784CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 785 cyclopropylmethyl H OCH₂CH₃ Cl 4-chlorophenyl 786 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-chlorophenyl 787OCH₂CH₃ H O CH₂CH₃ Cl 4-chlorophenyl 788 (CH₂)₂ O CH₂CH₃ Cl4-chlorophenyl 789 (CH₂)₄ O CH₂CH₃ Cl 4-chlorophenyl 790 CH₃ H O CH₂CH₃Cl 4-trifluoromethylphenyl 791 CH₂CH₃ H O CH₂CH₃ Cl4-trifluoromethylphenyl 792 CH₂CF₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl793 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-trifluoromethylphenyl 794 CH₂CH(CH₃)₂ H OCH₂CH₃ Cl 4-trifluoromethylphenyl 795 cyclopropylmethyl H O CH₂CH₃ Cl4-trifluoromethylphenyl 796 SCH(CH₃)₂ H O CH₂CH₃ Cl4-trifluoromethylphenyl 797 OCH₂CH₃ H O CH₂CH₃ Cl4-trifluoromethylphenyl 798 (CH₂)₂ O CH₂CH₃ Cl 4-trifluoromethylphenyl799 (CH₂)₄ O CH₂CH₃ Cl 4-trifluoromethylphenyl 800 CH₃ H O CH₂CH₃ Cl4-methoxyphenyl 801 CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 802 CH₂CF₃ H OCH₂CH₃ Cl 4-methoxyphenyl 803 CH₂CH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl804 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl 805 cyclopropylmethyl H OCH₂CH₃ Cl 4-methoxyphenyl 806 SCH(CH₃)₂ H O CH₂CH₃ Cl 4-methoxyphenyl807 OCH₂CH₃ H O CH₂CH₃ Cl 4-methoxyphenyl 808 (CH₂)₂ O CH₂CH₃ Cl4-methoxyphenyl 809 (CH₂)₄ O CH₂CH₃ Cl 4-methoxyphenyl 810 CH₃ H OCH₂CH₃ Cl 3,4 dichloro phenyl 811 CH₂CH₃ H O CH₂CH₃ Cl 3,4 dichlorophenyl 812 CH₂CF₃ H O CH₂CH₃ Cl 3,4 dichloro phenyl 813 CH₂CH₂CH₃ H OCH₂CH₃ Cl 3,4 dichloro phenyl 814 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichlorophenyl 815 cyclopropylmethyl H O CH₂CH₃ Cl 3,4 dichloro phenyl 816SCH(CH₃)₂ H O CH₂CH₃ Cl 3,4 dichloro phenyl 817 OCH₂CH₃ H O CH₂CH₃ Cl3,4 dichloro phenyl 818 (CH₂)₂ O CH₂CH₃ Cl 3,4 dichloro phenyl 819(CH₂)₄ O CH₂CH₃ Cl 3,4 dichloro phenyl 820 CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 821 CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 822 CH₂CF₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 823 CH₂CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 824 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 825 cyclopropylmethyl H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 826 SCH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 827 OCH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 828 (CH₂)₂ O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 829 (CH₂)₄ O CH₂CH₃ Cl5-benzo[c][1,2,5]oxadiazolyl 830 CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 831 CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 832 CH₂CF₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 833 CH₂CH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 834 CH₂CH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 835 cyclopropylmethyl H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 836 SCH(CH₃)₂ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 837 OCH₂CH₃ H O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 838 (CH₂)₂ O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 839 (CH₂)₄ O CH₂CH₃ Cl5-benzo[c][1,2,5]thiadiazolyl 840 CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 841CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 842 CH₂CF₃ H O CH₂CF₃ Cl4-fluorophenyl 843 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 844CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 845 cyclopropylmethyl H OCH₂CF₃ Cl 4-fluorophenyl 846 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-fluorophenyl 847OCH₂CH₃ H O CH₂CF₃ Cl 4-fluorophenyl 848 (CH₂)₂ O CH₂CF₃ Cl4-fluorophenyl 849 (CH₂)₄ O CH₂CF₃ Cl 4-fluorophenyl 850 CH₃ H O CH₂CF₃Cl 4-chlorophenyl 851 CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 852 CH₂CF₃ H OCH₂CF₃ Cl 4-chlorophenyl 853 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 854CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 855 cyclopropylmethyl H OCH₂CF₃ Cl 4-chlorophenyl 856 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-chlorophenyl 857OCH₂CH₃ H O CH₂CF₃ Cl 4-chlorophenyl 858 (CH₂)₂ O CH₂CF₃ Cl4-chlorophenyl 859 (CH₂)₄ O CH₂CF₃ Cl 4-chlorophenyl 860 CH₃ H O CH₂CF₃Cl 4-trifluoromethylphenyl 861 CH₂CH₃ H O CH₂CF₃ Cl4-trifluoromethylphenyl 862 CH₂CF₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl863 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 864 CH₂CH(CH₃)₂ H OCH₂CF₃ Cl 4-trifluoromethylphenyl 865 cyclopropylmethyl H O CH₂CF₃ Cl4-trifluoromethylphenyl 866 SCH(CH₃)₂ H O CH₂CF₃ Cl4-trifluoromethylphenyl 867 OCH₂CH₃ H O CH₂CF₃ Cl4-trifluoromethylphenyl 868 (CH₂)₂ O CH₂CF₃ Cl 4-trifluoromethylphenyl869 (CH₂)₄ O CH₂CF₃ Cl 4-trifluoromethylphenyl 870 CH₃ H O CH₂CF₃ Cl4-methoxyphenyl 871 CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 872 CH₂CF₃ H OCH₂CF₃ Cl 4-methoxyphenyl 873 CH₂CH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl874 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl 875 cyclopropylmethyl H OCH₂CF₃ Cl 4-methoxyphenyl 876 SCH(CH₃)₂ H O CH₂CF₃ Cl 4-methoxyphenyl877 OCH₂CH₃ H O CH₂CF₃ Cl 4-methoxyphenyl 878 (CH₂)₂ O CH₂CF₃ Cl4-methoxyphenyl 879 (CH₂)₄ O CH₂CF₃ Cl 4-methoxyphenyl 880 CH₃ H OCH₂CF₃ Cl 3,4 dichloro phenyl 881 CH₂CH₃ H O CH₂CF₃ Cl 3,4 dichlorophenyl 882 CH₂CF₃ H O CH₂CF₃ Cl 3,4 dichloro phenyl 883 CH₂CH₂CH₃ H OCH₂CF₃ Cl 3,4 dichloro phenyl 884 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichlorophenyl 885 cyclopropylmethyl H O CH₂CF₃ Cl 3,4 dichloro phenyl 886SCH(CH₃)₂ H O CH₂CF₃ Cl 3,4 dichloro phenyl 887 OCH₂CH₃ H O CH₂CF₃ Cl3,4 dichloro phenyl 888 (CH₂)₂ O CH₂CF₃ Cl 3,4 dichloro phenyl 889(CH₂)₄ O CH₂CF₃ Cl 3,4 dichloro phenyl 890 CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 891 CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 892 CH₂CF₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 893 CH₂CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 894 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 895 cyclopropylmethyl H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 896 SCH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 897 OCH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 898 (CH₂)₂ O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 899 (CH₂)₄ O CH₂CF₃ Cl5-benzo[c][1,2,5]oxadiazolyl 900 CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 901 CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 902 CH₂CF₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 903 CH₂CH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 904 CH₂CH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 905 cyclopropylmethyl H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 906 SCH(CH₃)₂ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 907 OCH₂CH₃ H O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 908 (CH₂)₂ O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 909 (CH₂)₄ O CH₂CF₃ Cl5-benzo[c][1,2,5]thiadiazolyl 910 CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 911CH₂CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 912 CH₂CF₃ H O CH₂-c-Pr Cl4-fluorophenyl 913 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 914CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-fluorophenyl 915 cyclopropylmethyl H OCH₂-c-Pr Cl 4-fluorophenyl 916 SCH(CH₃)₂ H O CH₂-c-Pr Cl 4-fluorophenyl917 OCH₂CH₃ H O CH₂-c-Pr Cl 4-fluorophenyl 918 (CH₂)₂ O CH₂-c-Pr Cl4-fluorophenyl 919 (CH₂)₄ O CH₂-c-Pr Cl 4-fluorophenyl 920 CH₃ H OCH₂-c-Pr Cl 4-chlorophenyl 921 CH₂CH₃ H O CH₂-c-Pr Cl 4-chlorophenyl 922CH₂CF₃ H O CH₂-c-Pr Cl 4-chlorophenyl 923 CH₂CH₂CH₃ H O CH₂-c-Pr Cl4-chlorophenyl 924 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-chlorophenyl 925cyclopropylmethyl H O CH₂-c-Pr Cl 4-chlorophenyl 926 SCH(CH₃)₂ H OCH₂-c-Pr Cl 4-chlorophenyl 927 OCH₂CH₃ H O CH₂-c-Pr Cl 4-chlorophenyl928 (CH₂)₂ O CH₂-c-Pr Cl 4-chlorophenyl 929 (CH₂)₄ O CH₂-c-Pr Cl4-chlorophenyl 930 CH₃ H O CH₂-c-Pr Cl 4-trifluoromethylphenyl 931CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoromethylphenyl 932 CH₂CF₃ H O CH₂-c-PrCl 4-trifluoromethylphenyl 933 CH₂CH₂CH₃ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 934 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 935 cyclopropylmethyl H O CH₂-c-Pr Cl4-trifluoromethylphenyl 936 SCH(CH₃)₂ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 937 OCH₂CH₃ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 938 (CH₂)₂ O CH₂-c-Pr Cl 4-trifluoromethylphenyl939 (CH₂)₄ O CH₂-c-Pr Cl 4-trifluoromethylphenyl 940 CH₃ H O CH₂-c-Pr Cl4-methoxyphenyl 941 CH₂CH₃ H O CH₂-c-Pr Cl 4-methoxyphenyl 942 CH₂CF₃ HO CH₂-c-Pr Cl 4-methoxyphenyl 943 CH₂CH₂CH₃ H O CH₂-c-Pr Cl4-methoxyphenyl 944 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-methoxyphenyl 945cyclopropylmethyl H O CH₂-c-Pr Cl 4-methoxyphenyl 946 SCH(CH₃)₂ H OCH₂-c-Pr Cl 4-methoxyphenyl 947 OCH₂CH₃ H O CH₂-c-Pr Cl 4-methoxyphenyl948 (CH₂)₂ O CH₂-c-Pr Cl 4-methoxyphenyl 949 (CH₂)₄ O CH₂-c-Pr Cl4-methoxyphenyl 950 CH₃ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 951 CH₂CH₃ HO CH₂-c-Pr Cl 3,4 dichloro phenyl 952 CH₂CF₃ H O CH₂-c-Pr Cl 3,4dichloro phenyl 953 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 954CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 955 cyclopropylmethyl HO CH₂-c-Pr Cl 3,4 dichloro phenyl 956 SCH(CH₃)₂ H O CH₂-c-Pr Cl 3,4dichloro phenyl 957 OCH₂CH₃ H O CH₂-c-Pr Cl 3,4 dichloro phenyl 958(CH₂)₂ O CH₂-c-Pr Cl 3,4 dichloro phenyl 959 (CH₂)₄ O CH₂-c-Pr Cl 3,4dichloro phenyl 960 CH₃ H O CH₂-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 961CH₂CH₃ H O CH₂-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 962 CH₂CF₃ H OCH₂-c-Pr Cl 5-benzo[c][1,2,5]oxadiazolyl 963 CH₂CH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 964 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 965 cyclopropylmethyl H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 966 SCH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 967 OCH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 968 (CH₂)₂ O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 969 (CH₂)₄ O CH₂-c-Pr Cl5-benzo[c][1,2,5]oxadiazolyl 970 CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 971 CH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 972 CH₂CF₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 973 CH₂CH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 974 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 975 cyclopropylmethyl H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 976 SCH(CH₃)₂ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 977 OCH₂CH₃ H O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 978 (CH₂)₂ O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl 979 (CH₂)₄ O CH₂-c-Pr Cl5-benzo[c][1,2,5]thiadiazolyl

TABLE 3 Compounds of Formula III Ex R1 R2 Y R4 R5 Z 980 CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoromethylphenyl 981 CH₂CF₃ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 982 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 983 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 984 cyclopropylmethyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 985 cyclobutylmethyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 986 (CH₂)₂ O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl987 (CH₂)₃ O CH₂ CF₃ CF₃ 4-trifluoromethylphenyl 988 (CH₂)₄ O CH₂ CF₃CF₃ 4-trifluoromethylphenyl 989 (CH₂)₅ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 990 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-trifluoromethylphenyl 991 Cyclopentyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 992 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl 993 CH₂CF₃ HO CH₂ CF₃ CF₃ 4-tolyl 994 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl 995CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-tolyl 996 cyclopropylmethyl H O CH₂ CF₃CF₃ 4-tolyl 997 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-tolyl 998 (CH₂)₂ OCH₂ CF₃ CF₃ 4-tolyl 999 (CH₂)₃ O CH₂ CF₃ CF₃ 4-tolyl 1000 (CH₂)₄ O CH₂CF₃ CF₃ 4-tolyl 1001 (CH₂)₅ O CH₂ CF₃ CF₃ 4-tolyl 10025,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-tolyl 1003 Cyclopentyl H O CH₂ CF₃CF₃ 4-tolyl 1004 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1005 CH₂CF₃ H OCH₂ CF₃ CF₃ 4-ethyl phenyl 1006 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl1007 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1008 cyclopropylmethyl HO CH₂ CF₃ CF₃ 4-ethyl phenyl 1009 cyclobutylmethyl H O CH₂ CF₃ CF₃4-ethyl phenyl 1010 (CH₂)₂ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1011 (CH₂)₃ OCH₂ CF₃ CF₃ 4-ethyl phenyl 1012 (CH₂)₄ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1013(CH₂)₅ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1014 5,5-spiro[2.3]hexane O CH₂ CF₃CF₃ 4-ethyl phenyl 1015 Cyclopentyl H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1016CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1017 CH₂CF₃ H O CH₂ CF₃ CF₃4-isopropyl phenyl 1018 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl1019 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1020cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1021cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1022 (CH₂)₂ O CH₂CF₃ CF₃ 4-isopropyl phenyl 1023 (CH₂)₃ O CH₂ CF₃ CF₃ 4-isopropyl phenyl1024 (CH₂)₄ O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1025 (CH₂)₅ O CH₂ CF₃ CF₃4-isopropyl phenyl 1026 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-isopropylphenyl 1027 Cyclopentyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1028 CH₂CH₃ HO CH₂ CF₃ CF₃ 4-thiomethylphenyl 1029 CH₂CF₃ H O CH₂ CF₃ CF₃4-thiomethylphenyl 1030 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl1031 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1032cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1033cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1034 (CH₂)₂ O CH₂CF₃ CF₃ 4-thiomethylphenyl 1035 (CH₂)₃ O CH₂ CF₃ CF₃ 4-thiomethylphenyl1036 (CH₂)₄ O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1037 (CH₂)₅ O CH₂ CF₃ CF₃4-thiomethylphenyl 1038 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-thiomethylphenyl 1039 Cyclopentyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl1040 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1041 CH₂CF₃ H O CH₂CF₃ CF₃ 4-trifluoromethoxyphenyl 1042 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1043 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1044 cyclopropylmethyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1045 cyclobutylmethyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1046 (CH₂)₂ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1047 (CH₂)₃ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1048 (CH₂)₄ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1049 (CH₂)₅ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1050 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1051 Cyclopentyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1052 CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1053 CH₂CF₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1054 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1055 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1056 cyclopropylmethy H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1057 cyclobutylmethyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1058 (CH₂)₂ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1059 (CH₂)₃ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1060 (CH₂)₄ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1061 (CH₂)₅ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1062 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1063 Cyclopentyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1064 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 1065 CH₂CF₃H O CH₂-c-Pr CF₃ 4-tolyl 1066 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 1067CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-tolyl 1068 cyclopropylmethyl H O CH₂-c-PrCF₃ 4-tolyl 1069 cyclobutylmethyl H O CH₂-c-Pr CF₃ 4-tolyl 1070 (CH₂)₂ OCH₂-c-Pr CF₃ 4-tolyl 1071 (CH₂)₃ O CH₂-c-Pr CF₃ 4-tolyl 1072 (CH₂)₄ OCH₂-c-Pr CF₃ 4-tolyl 1073 (CH₂)₅ O CH₂-c-Pr CF₃ 4-tolyl 10745,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-tolyl 1075 Cyclopentyl H OCH₂-c-Pr CF₃ 4-tolyl 1076 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1077CH₂CF₃ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1078 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-ethyl phenyl 1079 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1080cyclopropylmethyl H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1081 cyclobutylmethylH O CH₂-c-Pr CF₃ 4-ethyl phenyl 1082 (CH₂)₂ O CH₂-c-Pr CF₃ 4-ethylphenyl 1083 (CH₂)₃ O CH₂-c-Pr CF₃ 4-ethyl phenyl 1084 (CH₂)₄ O CH₂-c-PrCF₃ 4-ethyl phenyl 1085 (CH₂)₅ O CH₂-c-Pr CF₃ 4-ethyl phenyl 10865,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-ethyl phenyl 1087 Cyclopentyl H OCH₂-c-Pr CF₃ 4-ethyl phenyl 1088 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-isopropylphenyl 1089 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1090 CH₂CH₂CH₃ HO CH₂-c-Pr CF₃ 4-isopropyl phenyl 1091 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-isopropyl phenyl 1092 cyclopropylmethyl H O CH₂-c-Pr CF₃ 4-isopropylphenyl 1093 cyclobutylmethyl H O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1094(CH₂)₂ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1095 (CH₂)₃ O CH₂-c-Pr CF₃4-isopropyl phenyl 1096 (CH₂)₄ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1097(CH₂)₅ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1098 5,5-spiro[2.3]hexane OCH₂-c-Pr CF₃ 4-isopropyl phenyl 1099 Cyclopentyl H O CH₂-c-Pr CF₃4-isopropyl phenyl 1100 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1101CH₂CF₃ H O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1102 CH₂CH₂CH₃ H O CH₂-c-PrCF₃ 4-thiomethylphenyl 1103 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-thiomethylphenyl 1104 cyclopropylmethyl H O CH₂-c-Pr CF₃4-thiomethylphenyl 1105 cyclobutylmethyl H O CH₂-c-Pr CF₃4-thiomethylphenyl 1106 (CH₂)₂ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1107(CH₂)₃ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1108 (CH₂)₄ O CH₂-c-Pr CF₃4-thiomethylphenyl 1109 (CH₂)₅ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 11105,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1111 CyclopentylH O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1112 CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1113 CH₂CF₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1114 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1115 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1116 cyclopropylmethyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1117 cyclobutylmethyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1118 (CH₂)₂ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1119 (CH₂)₃ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1120 (CH₂)₄ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1121 (CH₂)₅ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1122 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1123 Cyclopentyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1124 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1125 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1126 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1127 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1128 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1129 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1130 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1131 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1132 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1133 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1134 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1135 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1136 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1137CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1138 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-tolyl 1139 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1140cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1141 cyclobutylmethyl H OCH₂ CF₃ OCH₂ CF₃ 4-tolyl 1142 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1143(CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1144 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl1145 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1146 5,5-spiro[2.3]hexane O CH₂CF₃ OCH₂ CF₃ 4-tolyl 1147 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1148CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1149 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 1150 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl1151 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1152cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1153cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1154 (CH₂)₂ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 1155 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-ethylphenyl 1156 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1157 (CH₂)₅ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 1158 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-ethyl phenyl 1159 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1160CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1161 CH₂CF₃ H O CH₂ CF₃OCH₂ CF₃ 4-isopropyl phenyl 1162 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-isopropyl phenyl 1163 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropylphenyl 1164 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl1165 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1166(CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1167 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 1168 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl1169 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 11705,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1171Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1172 CH₂CH₃ H O CH₂CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1173 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1174 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1175 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1176 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1177 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1178 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl1179 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1180 (CH₂)₄ O CH₂ CF₃OCH₂ CF₃ 4-thiomethylphenyl 1181 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1182 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1183 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1184 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1185 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1186 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1187 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1188 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1189 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1190 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1191 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1192 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1193 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1194 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1195 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1196 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1197 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1198 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1199 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1200 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1201 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1202 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1203 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1204 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1205 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1206 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1207 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1208 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1209CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1210 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1211 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1212cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1213 cyclobutylmethyl HO CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1214 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1215(CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1216 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-tolyl 1217 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 12185,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1219 Cyclopentyl H OCH₂-c-Pr OCH₂ CF₃ 4-tolyl 1220 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 1221 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1222 CH₂CH₂CH₃ HO CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1223 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 1224 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 1225 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1226(CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1227 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 1228 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1229(CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1230 5,5-spiro[2.3]hexane OCH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1231 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-ethyl phenyl 1232 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1233CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1234 CH₂CH₂CH₃ H OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1235 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl phenyl 1236 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1237 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1238 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl1239 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1240 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1241 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1242 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1243 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃ 4-isopropylphenyl 1244 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1245 CH₂CF₃H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1246 CH₂CH₂CH₃ H O CH₂-c-PrOCH₂ CF₃ 4-thiomethylphenyl 1247 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1248 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1249 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1250 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl1251 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1252 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1253 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1254 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1255 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1256 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1257 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1258 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1259 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1260 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1261 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1262 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1263 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1264 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1265 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1266 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1267 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl

TABLE 4 Compounds of Formula III Ex R1 R2 Y R4 R5 Z 1268cyclobutylmethyl H O CH₂ CF₃ Cl 4-trifluoromethylphenyl 1269 (CH₂)₃ OCH₂ CF₃ Cl 4-trifluoromethylphenyl 1270 (CH₂)₅ O CH₂ CF₃ Cl4-trifluoromethylphenyl 1271 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl4-trifluoromethylphenyl 1272 Cyclopentyl H O CH₂ CF₃ Cl4-trifluoromethylphenyl 1273 CH₂CH₃ H O CH₂ CF₃ Cl 4-tolyl 1274 CH₂CF₃ HO CH₂ CF₃ Cl 4-tolyl 1275 CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-tolyl 1276CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-tolyl 1277 cyclopropylmethyl H O CH₂ CF₃ Cl4-tolyl 1278 cyclobutylmethyl H O CH₂ CF₃ Cl 4-tolyl 1279 (CH₂)₂ O CH₂CF₃ Cl 4-tolyl 1280 (CH₂)₃ O CH₂ CF₃ Cl 4-tolyl 1281 (CH₂)₄ O CH₂ CF₃ Cl4-tolyl 1282 (CH₂)₅ O CH₂ CF₃ Cl 4-tolyl 1283 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 4-tolyl 1284 Cyclopentyl H O CH₂ CF₃ Cl 4-tolyl 1285 CH₂CH₃ H OCH₂ CF₃ Cl 4-ethyl phenyl 1286 CH₂CF₃ H O CH₂ CF₃ Cl 4-ethyl phenyl 1287CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-ethyl phenyl 1288 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-ethyl phenyl 1289 cyclopropylmethyl H O CH₂ CF₃ Cl 4-ethyl phenyl 1290cyclobutylmethyl H O CH₂ CF₃ Cl 4-ethyl phenyl 1291 (CH₂)₂ O CH₂ CF₃ Cl4-ethyl phenyl 1292 (CH₂)₃ O CH₂ CF₃ Cl 4-ethyl phenyl 1293 (CH₂)₄ O CH₂CF₃ Cl 4-ethyl phenyl 1294 (CH₂)₅ O CH₂ CF₃ Cl 4-ethyl phenyl 12955,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-ethyl phenyl 1296 Cyclopentyl H OCH₂ CF₃ Cl 4-ethyl phenyl 1297 CH₂CH₃ H O CH₂ CF₃ Cl 4-isopropyl phenyl1298 CH₂CF₃ H O CH₂ CF₃ Cl 4-isopropyl phenyl 1299 CH₂CH₂CH₃ H O CH₂ CF₃Cl 4-isopropyl phenyl 1300 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-isopropyl phenyl1301 cyclopropylmethyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 1302cyclobutylmethyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 1303 (CH₂)₂ O CH₂ CF₃Cl 4-isopropyl phenyl 1304 (CH₂)₃ O CH₂ CF₃ Cl 4-isopropyl phenyl 1305(CH₂)₄ O CH₂ CF₃ Cl 4-isopropyl phenyl 1306 (CH₂)₅ O CH₂ CF₃ Cl4-isopropyl phenyl 1307 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-isopropylphenyl 1308 Cyclopentyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 1309 CH₂CH₃ HO CH₂ CF₃ Cl 4-thiomethylphenyl 1310 CH₂CF₃ H O CH₂ CF₃ Cl4-thiomethylphenyl 1311 CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-thiomethylphenyl 1312CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-thiomethylphenyl 1313 cyclopropylmethyl H OCH₂ CF₃ Cl 4-thiomethylphenyl 1314 cyclobutylmethyl H O CH₂ CF₃ Cl4-thiomethylphenyl 1315 (CH₂)₂ O CH₂ CF₃ Cl 4-thiomethylphenyl 1316(CH₂)₃ O CH₂ CF₃ Cl 4-thiomethylphenyl 1317 (CH₂)₄ O CH₂ CF₃ Cl4-thiomethylphenyl 1318 (CH₂)₅ O CH₂ CF₃ Cl 4-thiomethylphenyl 13195,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-thiomethylphenyl 1320 Cyclopentyl HO CH₂ CF₃ Cl 4-thiomethylphenyl 1321 CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1322 CH₂CF₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1323 CH₂CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1324 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1325 cyclopropylmethyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1326 cyclobutylmethyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1327 (CH₂)₂ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1328 (CH₂)₃ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1329 (CH₂)₄ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1330 (CH₂)₅ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1331 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1332 Cyclopentyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1333 cyclobutylmethyl H O CH₂—c-Pr Cl4-trifluoromethylphenyl 1334 (CH₂)₃ O CH₂—c-Pr Cl4-trifluoromethylphenyl 1335 (CH₂)₅ O CH₂—c-Pr Cl4-trifluoromethylphenyl 1336 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl4-trifluoromethylphenyl 1337 Cyclopentyl H O CH₂—c-Pr Cl4-trifluoromethylphenyl 1338 CH₂CH₃ H O CH₂—c-Pr Cl 4-tolyl 1339 CH₂CF₃H O CH₂—c-Pr Cl 4-tolyl 1340 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-tolyl 1341CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-tolyl 1342 cyclopropylmethyl H O CH₂—c-PrCl 4-tolyl 1343 cyclobutylmethyl H O CH₂—c-Pr Cl 4-tolyl 1344 (CH₂)₂ OCH₂—c-Pr Cl 4-tolyl 1345 (CH₂)₃ O CH₂—c-Pr Cl 4-tolyl 1346 (CH₂)₄ OCH₂—c-Pr Cl 4-tolyl 1347 (CH₂)₅ O CH₂—c-Pr Cl 4-tolyl 13485,5-spiro[2.3]hexane O CH₂—c-Pr CI 4-tolyl 1349 Cyclopentyl H O CH₂—c-PrCl 4-tolyl 1350 CH₂CH₃ H O CH₂—c-Pr Cl 4-ethyl phenyl 1351 CH₂CF₃ H OCH₂—c-Pr Cl 4-ethyl phenyl 1352 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-ethyl phenyl1353 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-ethyl phenyl 1354 cyclopropylmethyl HO CH₂—c-Pr Cl 4-ethyl phenyl 1355 cyclobutylmethyl H O CH₂—c-Pr Cl4-ethyl phenyl 1356 (CH₂)₂ O CH₂—c-Pr Cl 4-ethyl phenyl 1357 (CH₂)₃ OCH₂—c-Pr Cl 4-ethyl phenyl 1358 (CH₂)₄ O CH₂—c-Pr Cl 4-ethyl phenyl 1359(CH₂)₅ O CH₂—c-Pr Cl 4-ethyl phenyl 1360 5,5-spiro[2.3]hexane O CH₂—c-PrCl 4-ethyl phenyl 1361 Cyclopentyl H O CH₂—c-Pr Cl 4-ethyl phenyl 1362CH₂CH₃ H O CH₂—c-Pr Cl 4-isopropyl phenyl 1363 CH₂CF₃ H O CH₂—c-Pr Cl4-isopropyl phenyl 1364 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-isopropyl phenyl1365 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-isopropyl phenyl 1366cyclopropylmethyl H O CH₂—c-Pr Cl 4-isopropyl phenyl 1367cyclobutylmethyl H O CH₂—c-Pr Cl 4-isopropyl phenyl 1368 (CH₂)₂ OCH₂—c-Pr Cl 4-isopropyl phenyl 1369 (CH₂)₃ O CH₂—c-Pr Cl 4-isopropylphenyl 1370 (CH₂)₄ O CH₂—c-Pr Cl 4-isopropyl phenyl 1371 (CH₂)₅ OCH₂—c-Pr Cl 4-isopropyl phenyl 1372 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl4-isopropyl phenyl 1373 Cyclopentyl H O CH₂—c-Pr Cl 4-isopropyl phenyl1374 CH₂CH₃ H O CH₂—c-Pr Cl 4-thiomethylphenyl 1375 CH₂CF₃ H O CH₂—c-PrCl 4-thiomethylphenyl 1376 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-thiomethylphenyl1377 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-thiomethylphenyl 1378cyclopropylmethyl H O CH₂—c-Pr Cl 4-thiomethylphenyl 1379cyclobutylmethyl H O CH₂—c-Pr Cl 4-thiomethylphenyl 1380 (CH₂)₂ OCH₂—c-Pr Cl 4-thiomethylphenyl 1381 (CH₂)₃ O CH₂—c-Pr Cl4-thiomethylphenyl 1382 (CH₂)₄ O CH₂—c-Pr Cl 4-thiomethylphenyl 1383(CH₂)₅ O CH₂—c-Pr Cl 4-thiomethylphenyl 1384 5,5-spiro[2.3]hexane OCH₂—c-Pr Cl 4-thiomethylphenyl 1385 Cyclopentyl H O CH₂—c-Pr Cl4-thiomethylphenyl 1386 CH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethoxyphenyl1387 CH₂CF₃ H O CH₂—c-Pr Cl 4-trifluoromethoxyphenyl 1388 CH₂CH₂CH₃ H OCH₂—c-Pr Cl 4-trifluoromethoxyphenyl 1389 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1390 cyclopropylmethyl H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1391 cyclobutylmethyl H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1392 (CH₂)₂ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1393 (CH₂)₃ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1394 (CH₂)₄ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1395 (CH₂)₅ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1396 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1397 Cyclopentyl H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 1398 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1399 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1400 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1401 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1402 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1403 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1404 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1405 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1406 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1407 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1408 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1409 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1410 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1411CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1412 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-tolyl 1413 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1414cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1415 cyclobutylmethyl H OCH₂ CF₃ OCH₂ CF₃ 4-tolyl 1416 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1417(CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1418 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl1419 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1420 5,5-spiro[2.3]hexane O CH₂CF₃ OCH₂ CF₃ 4-tolyl 1421 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1422CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1423 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 1424 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl1425 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1426cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1427cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1428 (CH₂)₂ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 1429 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-ethylphenyl 1430 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1431 (CH₂)₅ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 1432 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-ethyl phenyl 1433 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1434CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1435 CH₂CF₃ H O CH₂ CF₃OCH₂ CF₃ 4-isopropyl phenyl 1436 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-isopropyl phenyl 1437 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropylphenyl 1438 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl1439 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1440(CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1441 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 1442 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl1443 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 14445,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1445Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1446 CH₂CH₃ H O CH₂CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1447 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1448 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1449 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1450 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1451 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1452 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl1453 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1454 (CH₂)₄ O CH₂ CF₃OCH₂ CF₃ 4-thiomethylphenyl 1455 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1456 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1457 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1458 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1459 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1460 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1461 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1462 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1463 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1464 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1465 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1466 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1467 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1468 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1469 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1470 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1471 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1472 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1473 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1474 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1475 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1476 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1477 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1478 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1479 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1480 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1481 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1482 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1483CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1484 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃ 4-tolyl 1485 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1486cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1487 cyclobutylmethyl HO CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1488 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1489(CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1490 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃4-tolyl 1491 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 14925,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃ 4-tolyl 1493 Cyclopentyl H OCH₂—c-Pr OCH₂ CF₃ 4-tolyl 1494 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-ethylphenyl 1495 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1496 CH₂CH₂CH₃ HO CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1497 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 1498 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-ethylphenyl 1499 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1500(CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1501 (CH₂)₃ O CH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 1502 (CH₂)₄ O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1503(CH₂)₅ O CH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1504 5,5-spiro[2.3]hexane OCH₂—c-Pr OCH₂ CF₃ 4-ethyl phenyl 1505 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃4-ethyl phenyl 1506 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1507CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1508 CH₂CH₂CH₃ H OCH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1509 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃ 4-isopropyl phenyl 1510 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃4-isopropyl phenyl 1511 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃4-isopropyl phenyl 1512 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl1513 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1514 (CH₂)₄ OCH₂—c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1515 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃4-isopropyl phenyl 1516 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃4-isopropyl phenyl 1517 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃ 4-isopropylphenyl 1518 CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1519 CH₂CF₃H O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1520 CH₂CH₂CH₃ H O CH₂—c-PrOCH₂ CF₃ 4-thiomethylphenyl 1521 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃4-thiomethylphenyl 1522 cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃4-thiomethylphenyl 1523 cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃4-thiomethylphenyl 1524 (CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl1525 (CH₂)₃ O CH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1526 (CH₂)₄ OCH₂—c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1527 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃4-thiomethylphenyl 1528 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃4-thiomethylphenyl 1529 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃4-thiomethylphenyl CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl1530 CH₂CF₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1531CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1532CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1533cyclopropylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1534cyclobutylmethyl H O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1535(CH₂)₂ O CH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1536 (CH₂)₃ OCH₂—c-Pr OCH₂ CF₃ 4-trifluoromethoxyphenyl 1537 (CH₂)₄ O CH₂—c-Pr OCH₂CF₃ 4-trifluoromethoxyphenyl 1538 (CH₂)₅ O CH₂—c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1539 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1540 Cyclopentyl H O CH₂—c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl

TABLE 5 Compounds of Formula IV Ex R1 R2 X R3 R5 Z 1541 CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoromethylphenyl 1542 CH₂CF₃ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1543 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1544 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1545 cyclopropylmethyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1546 cyclobutylmethyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1547 (CH₂)₂ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1548 (CH₂)₃ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1549 (CH₂)₄ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1550 (CH₂)₅ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1551 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1552 Cyclopentyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 1553 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl 1554 CH₂CF₃H O CH₂ CF₃ CF₃ 4-tolyl 1555 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl 1556CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-tolyl 1557 cyclopropylmethyl H O CH₂ CF₃CF₃ 4-tolyl 1558 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-tolyl 1559 (CH₂)₂ OCH₂ CF₃ CF₃ 4-tolyl 1560 (CH₂)₃ O CH₂ CF₃ CF₃ 4-tolyl 1561 (CH₂)₄ O CH₂CF₃ CF₃ 4-tolyl 1562 (CH₂)₅ O CH₂ CF₃ CF₃ 4-tolyl 15635,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-tolyl 1564 Cyclopentyl H O CH₂ CF₃CF₃ 4-tolyl 1565 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1566 CH₂CF₃ H OCH₂ CF₃ CF₃ 4-ethyl phenyl 1567 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl1568 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1569 cyclopropylmethyl HO CH₂ CF₃ CF₃ 4-ethyl phenyl 1570 cyclobutylmethyl H O CH₂ CF₃ CF₃4-ethyl phenyl 1571 (CH₂)₂ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1572 (CH₂)₃ OCH₂ CF₃ CF₃ 4-ethyl phenyl 1573 (CH₂)₄ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1574(CH₂)₅ O CH₂ CF₃ CF₃ 4-ethyl phenyl 1575 5,5-spiro[2.3]hexane O CH₂ CF₃CF₃ 4-ethyl phenyl 1576 Cyclopentyl H O CH₂ CF₃ CF₃ 4-ethyl phenyl 1577CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1578 CH₂CF₃ H O CH₂ CF₃ CF₃4-isopropyl phenyl 1579 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl1580 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1581cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1582cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1583 (CH₂)₂ O CH₂CF₃ CF₃ 4-isopropyl phenyl 1584 (CH₂)₃ O CH₂ CF₃ CF₃ 4-isopropyl phenyl1585 (CH₂)₄ O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1586 (CH₂)₅ O CH₂ CF₃ CF₃4-isopropyl phenyl 1587 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-isopropylphenyl 1588 Cyclopentyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 1589 CH₂CH₃ HO CH₂ CF₃ CF₃ 4-thiomethylphenyl 1590 CH₂CF₃ H O CH₂ CF₃ CF₃4-thiomethylphenyl 1591 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl1592 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1593cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1594cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1595 (CH₂)₂ O CH₂CF₃ CF₃ 4-thiomethylphenyl 1596 (CH₂)₃ O CH₂ CF₃ CF₃ 4-thiomethylphenyl1597 (CH₂)₄ O CH₂ CF₃ CF₃ 4-thiomethylphenyl 1598 (CH₂)₅ O CH₂ CF₃ CF₃4-thiomethylphenyl 1599 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-thiomethylphenyl 1600 Cyclopentyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl1601 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 1602 CH₂CF₃ H O CH₂CF₃ CF₃ 4-trifluoromethoxyphenyl 1603 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1604 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1605 cyclopropylmethyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1606 cyclobutylmethyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1607 (CH₂)₂ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1608 (CH₂)₃ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1609 (CH₂)₄ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1610 (CH₂)₅ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1611 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1612 Cyclopentyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 1613 CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1614 CH₂CF₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1615 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1616 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1617 cyclopropylmethyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1618 cyclobutylmethyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1619 (CH₂)₂ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1620 (CH₂)₃ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1621 (CH₂)₄ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1622 (CH₂)₅ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1623 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1624 Cyclopentyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 1625 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 1626 CH₂CF₃H O CH₂-c-Pr CF₃ 4-tolyl 1627 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 1628CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-tolyl 1629 cyclopropylmethyl H O CH₂-c-PrCF₃ 4-tolyl 1630 cyclobutylmethyl H O CH₂-c-Pr CF₃ 4-tolyl 1631 (CH₂)₂ OCH₂-c-Pr CF₃ 4-tolyl 1632 (CH₂)₃ O CH₂-c-Pr CF₃ 4-tolyl 1633 (CH₂)₄ OCH₂-c-Pr CF₃ 4-tolyl 1634 (CH₂)₅ O CH₂-c-Pr CF₃ 4-tolyl 16355,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-tolyl 1636 Cyclopentyl H OCH₂-c-Pr CF₃ 4-tolyl 1637 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1638CH₂CF₃ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1639 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-ethyl phenyl 1640 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1641cyclopropylmethyl H O CH₂-c-Pr CF₃ 4-ethyl phenyl 1642 cyclobutylmethylH O CH₂-c-Pr CF₃ 4-ethyl phenyl 1643 (CH₂)₂ O CH₂-c-Pr CF₃ 4-ethylphenyl 1644 (CH₂)₃ O CH₂-c-Pr CF₃ 4-ethyl phenyl 1645 (CH₂)₄ O CH₂-c-PrCF₃ 4-ethyl phenyl 1646 (CH₂)₅ O CH₂-c-Pr CF₃ 4-ethyl phenyl 16475,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-ethyl phenyl 1648 Cyclopentyl H OCH₂-c-Pr CF₃ 4-ethyl phenyl 1649 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-isopropylphenyl 1650 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1651 CH₂CH₂CH₃ HO CH₂-c-Pr CF₃ 4-isopropyl phenyl 1652 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-isopropyl phenyl 1653 cyclopropylmethyl H O CH₂-c-Pr CF₃ 4-isopropylphenyl 1654 cyclobutylmethyl H O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1655(CH₂)₂ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1656 (CH₂)₃ O CH₂-c-Pr CF₃4-isopropyl phenyl 1657 (CH₂)₄ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1658(CH₂)₅ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 1659 5,5-spiro[2.3]hexane OCH₂-c-Pr CF₃ 4-isopropyl phenyl 1660 Cyclopentyl H O CH₂-c-Pr CF₃4-isopropyl phenyl 1661 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1662CH₂CF₃ H O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1663 CH₂CH₂CH₃ H O CH₂-c-PrCF₃ 4-thiomethylphenyl 1664 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-thiomethylphenyl 1665 cyclopropylmethyl H O CH₂-c-Pr CF₃4-thiomethylphenyl 1666 cyclobutylmethyl H O CH₂-c-Pr CF₃4-thiomethylphenyl 1667 (CH₂)₂ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1668(CH₂)₃ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1669 (CH₂)₄ O CH₂-c-Pr CF₃4-thiomethylphenyl 1670 (CH₂)₅ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 16715,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1672 CyclopentylH O CH₂-c-Pr CF₃ 4-thiomethylphenyl 1673 CH₂CF₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1674 CH₂CF₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1675 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1676 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1677 cyclopropylmethyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1678 cyclobutylmethyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1679 (CH₂)₂ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1680 (CH₂)₃ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1681 (CH₂)₄ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1682 (CH₂)₅ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1683 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1684 Cyclopentyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 1685 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1686 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1687 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1688 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1689 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1690 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1691 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1692 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1693 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1694 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1695 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1696 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1697 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1698CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1699 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-tolyl 1700 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1701cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1702 cyclobutylmethyl H OCH₂ CF₃ OCH₂ CF₃ 4-tolyl 1703 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1704(CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1705 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl1706 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1707 5,5-spiro[2.3]hexane O CH₂CF₃ OCH₂ CF₃ 4-tolyl 1708 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1709CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1710 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 1711 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl1712 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1713cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1714cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1715 (CH₂)₂ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 1716 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-ethylphenyl 1717 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1718 (CH₂)₅ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 1719 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-ethyl phenyl 1720 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1721CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1722 CH₂CF₃ H O CH₂ CF₃OCH₂ CF₃ 4-isopropyl phenyl 1723 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-isopropyl phenyl 1724 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropylphenyl 1725 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl1726 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1727(CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1728 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 1729 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl1730 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 17315,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1732Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 1733 CH₂CH₃ H O CH₂CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1734 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1735 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1736 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1737 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1738 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1739 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl1740 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 1741 (CH₂)₄ O CH₂ CF₃OCH₂ CF₃ 4-thiomethylphenyl 1742 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1743 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1744 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 1745 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1746 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1747 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1748 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1749 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1750 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1751 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1752 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1753 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1754 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1755 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1756 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 1757 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1758 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1759 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1760 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1761 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1762 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1763 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1764 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1765 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1766 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1767 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1768 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 1769 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1770CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1771 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 1772 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1773cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1774 cyclobutylmethyl HO CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1775 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1776(CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1777 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-tolyl 1778 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 17795,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 1780 Cyclopentyl H OCH₂-c-Pr OCH₂ CF₃ 4-tolyl 1781 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 1782 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1783 CH₂CH₂CH₃ HO CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1784 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 1785 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 1786 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1787(CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1788 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 1789 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1790(CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1791 5,5-spiro[2.3]hexane OCH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 1792 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-ethyl phenyl 1793 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1794CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1795 CH₂CH₂CH₃ H OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1796 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl phenyl 1797 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1798 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1799 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl1800 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1801 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 1802 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1803 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 1804 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃ 4-isopropylphenyl 1805 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1806 CH₂CF₃H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1807 CH₂CH₂CH₃ H O CH₂-c-PrOCH₂ CF₃ 4-thiomethylphenyl 1808 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1809 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1810 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1811 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl1812 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1813 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 1814 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1815 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1816 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 1817 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1818 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1819 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1820 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1821 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1822 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1823 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1824 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1825 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1826 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1827 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 1828 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl

TABLE 6 Compounds of Formula IV Ex R1 R2 X R3 R5 Z 1829 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 1830 CH₂CF₃ H O CH₂ CF₃ Cl4-trifluoromethylphenyl 1831 CH₂CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethylphenyl 1832 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-trifluoromethylphenyl 1833 cyclopropylmethyl H O CH₂ CF₃ Cl4-trifluoromethylphenyl 1834 cyclobutylmethyl H O CH₂ CF₃ Cl4-trifluoromethylphenyl 1835 (CH₂)₂ O CH₂ CF₃ Cl 4-trifluoromethylphenyl1836 (CH₂)₃ O CH₂ CF₃ Cl 4-trifluoromethylphenyl 1837 (CH₂)₄ O CH₂ CF₃Cl 4-trifluoromethylphenyl 1838 (CH₂)₅ O CH₂ CF₃ Cl4-trifluoromethylphenyl 1839 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl4-trifluoromethylphenyl 1840 Cyclopentyl H O CH₂ CF₃ Cl4-trifluoromethylphenyl 1841 CH₂CH₃ H O CH₂ CF₃ Cl 4-tolyl 1842 CH₂CF₃ HO CH₂ CF₃ Cl 4-tolyl 1843 CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-tolyl 1844CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-tolyl 1845 cyclopropylmethyl H O CH₂ CF₃ Cl4-tolyl 1846 cyclobutylmethyl H O CH₂ CF₃ Cl 4-tolyl 1847 (CH₂)₂ O CH₂CF₃ Cl 4-tolyl 1848 (CH₂)₃ O CH₂ CF₃ Cl 4-tolyl 1849 (CH₂)₄ O CH₂ CF₃ Cl4-tolyl 1850 (CH₂)₅ O CH₂ CF₃ Cl 4-tolyl 1851 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 4-tolyl 1852 Cyclopentyl H O CH₂ CF₃ Cl 4-tolyl 1853 CH₂CH₃ H OCH₂ CF₃ Cl 4-ethyl phenyl 1854 CH₂CF₃ H O CH₂ CF₃ Cl 4-ethyl phenyl 1855CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-ethyl phenyl 1856 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-ethyl phenyl 1857 cyclopropylmethyl H O CH₂ CF₃ Cl 4-ethyl phenyl 1858cyclobutylmethyl H O CH₂ CF₃ Cl 4-ethyl phenyl 1859 (CH₂)₂ O CH₂ CF₃ Cl4-ethyl phenyl 1860 (CH₂)₃ O CH₂ CF₃ Cl 4-ethyl phenyl 1861 (CH₂)₄ O CH₂CF₃ Cl 4-ethyl phenyl 1862 (CH₂)₅ O CH₂ CF₃ Cl 4-ethyl phenyl 18635,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-ethyl phenyl 1864 Cyclopentyl H OCH₂ CF₃ Cl 4-ethyl phenyl 1865 CH₂CH₃ H O CH₂ CF₃ Cl 4-isopropyl phenyl1866 CH₂CF₃ H O CH₂ CF₃ Cl 4-isopropyl phenyl 1867 CH₂CH₂CH₃ H O CH₂ CF₃Cl 4-isopropyl phenyl 1868 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-isopropyl phenyl1869 cyclopropylmethyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 1870cyclobutylmethyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 1871 (CH₂)₂ O CH₂ CF₃Cl 4-isopropyl phenyl 1872 (CH₂)₃ O CH₂ CF₃ Cl 4-isopropyl phenyl 1873(CH₂)₄ O CH₂ CF₃ Cl 4-isopropyl phenyl 1874 (CH₂)₅ O CH₂ CF₃ Cl4-isopropyl phenyl 1875 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-isopropylphenyl 1876 Cyclopentyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 1877 CH₂CH₃ HO CH₂ CF₃ Cl 4-thiomethylphenyl 1878 CH₂CF₃ H O CH₂ CF₃ Cl4-thiomethylphenyl 1879 CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-thiomethylphenyl 1880CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-thiomethylphenyl 1881 cyclopropylmethyl H OCH₂ CF₃ Cl 4-thiomethylphenyl 1882 cyclobutylmethyl H O CH₂ CF₃ Cl4-thiomethylphenyl 1883 (CH₂)₂ O CH₂ CF₃ Cl 4-thiomethylphenyl 1884(CH₂)₃ O CH₂ CF₃ Cl 4-thiomethylphenyl 1885 (CH₂)₄ O CH₂ CF₃ Cl4-thiomethylphenyl 1886 (CH₂)₅ O CH₂ CF₃ Cl 4-thiomethylphenyl 18875,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-thiomethylphenyl 1888 Cyclopentyl HO CH₂ CF₃ Cl 4-thiomethylphenyl 1889 CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1890 CH₂CF₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1891 CH₂CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1892 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1893 cyclopropylmethyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1894 cyclobutylmethyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1895 (CH₂)₂ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1896 (CH₂)₃ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1897 (CH₂)₄ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1898 (CH₂)₅ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1899 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1900 Cyclopentyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 1901 CH₂CH₃ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 1902 CH₂CF₃ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 1903 CH₂CH₂CH₃ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 1904 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl4-trifluoromethylphenyl 1905 cyclopropylmethyl H O CH₂-c-Pr Cl4-trifluoromethylphenyl 1906 cyclobutylmethyl H O CH₂-c-Pr Cl4-trifluoromethylphenyl 1907 (CH₂)₂ O CH₂-c-Pr Cl4-trifluoromethylphenyl 1908 (CH₂)₃ O CH₂-c-Pr Cl4-trifluoromethylphenyl 1909 (CH₂)₄ O CH₂-c-Pr Cl4-trifluoromethylphenyl 1910 (CH₂)₅ O CH₂-c-Pr Cl4-trifluoromethylphenyl 1911 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl4-trifluoromethylphenyl 1912 Cyclopentyl H O CH₂-c-Pr Cl4-trifluoromethylphenyl 1913 CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 1914 CH₂CF₃H O CH₂-c-Pr Cl 4-tolyl 1915 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-tolyl 1916CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-tolyl 1917 cyclopropylmethyl H O CH₂-c-PrCl 4-tolyl 1918 cyclobutylmethyl H O CH₂-c-Pr Cl 4-tolyl 1919 (CH₂)₂ OCH₂-c-Pr Cl 4-tolyl 1920 (CH₂)₃ O CH₂-c-Pr Cl 4-tolyl 1921 (CH₂)₄ OCH₂-c-Pr Cl 4-tolyl 1922 (CH₂)₅ O CH₂-c-Pr Cl 4-tolyl 19235,5-spiro[2.3]hexane O CH₂-c-Pr Cl 4-tolyl 1924 Cyclopentyl H O CH₂-c-PrCl 4-tolyl 1925 CH₂CH₃ H O CH₂-c-Pr Cl 4-ethyl phenyl 1926 CH₂CF₃ H OCH₂-c-Pr Cl 4-ethyl phenyl 1927 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-ethyl phenyl1928 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-ethyl phenyl 1929 cyclopropylmethyl HO CH₂-c-Pr Cl 4-ethyl phenyl 1930 cyclobutylmethyl H O CH₂-c-Pr Cl4-ethyl phenyl 1931 (CH₂)₂ O CH₂-c-Pr Cl 4-ethyl phenyl 1932 (CH₂)₃ OCH₂-c-Pr Cl 4-ethyl phenyl 1933 (CH₂)₄ O CH₂-c-Pr Cl 4-ethyl phenyl 1934(CH₂)₅ O CH₂-c-Pr Cl 4-ethyl phenyl 1935 5,5-spiro[2.3]hexane O CH₂-c-PrCl 4-ethyl phenyl 1936 Cyclopentyl H O CH₂-c-Pr Cl 4-ethyl phenyl 1937CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl phenyl 1938 CH₂CF₃ H O CH₂-c-Pr Cl4-isopropyl phenyl 1939 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-isopropyl phenyl1940 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-isopropyl phenyl 1941cyclopropylmethyl H O CH₂-c-Pr Cl 4-isopropyl phenyl 1942cyclobutylmethyl H O CH₂-c-Pr Cl 4-isopropyl phenyl 1943 (CH₂)₂ OCH₂-c-Pr Cl 4-isopropyl phenyl 1944 (CH₂)₃ O CH₂-c-Pr Cl 4-isopropylphenyl 1945 (CH₂)₄ O CH₂-c-Pr Cl 4-isopropyl phenyl 1946 (CH₂)₅ OCH₂-c-Pr Cl 4-isopropyl phenyl 1947 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl4-isopropyl phenyl 1948 Cyclopentyl H O CH₂-c-Pr Cl 4-isopropyl phenyl1949 CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethylphenyl 1950 CH₂CF₃ H O CH₂-c-PrCl 4-thiomethylphenyl 1951 CH₂CH₂CH₃ H O CH₂-c-Pr Cl 4-thiomethylphenyl1952 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl 4-thiomethylphenyl 1953cyclopropylmethyl H O CH₂-c-Pr Cl 4-thiomethylphenyl 1954cyclobutylmethyl H O CH₂-c-Pr Cl 4-thiomethylphenyl 1955 (CH₂)₂ OCH₂-c-Pr Cl 4-thiomethylphenyl 1956 (CH₂)₃ O CH₂-c-Pr Cl4-thiomethylphenyl 1957 (CH₂)₄ O CH₂-c-Pr Cl 4-thiomethylphenyl 1958(CH₂)₅ O CH₂-c-Pr Cl 4-thiomethylphenyl 1959 5,5-spiro[2.3]hexane OCH₂-c-Pr Cl 4-thiomethylphenyl 1960 Cyclopentyl H O CH₂-c-Pr Cl4-thiomethylphenyl 1961 CH₂CH₃ H O CH₂-c-Pr Cl 4-trifluoromethoxyphenyl1962 CH₂CF₃ H O CH₂-c-Pr Cl 4-trifluoromethoxyphenyl 1963 CH₂CH₂CH₃ H OCH₂-c-Pr Cl 4-trifluoromethoxyphenyl 1964 CH₂CH(CH₃)₂ H O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1965 cyclopropylmethyl H O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1966 cyclobutylmethyl H O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1967 (CH₂)₂ O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1968 (CH₂)₃ O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1969 (CH₂)₄ O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1970 (CH₂)₅ O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1971 5,5-spiro[2.3]hexane O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1972 Cyclopentyl H O CH₂-c-Pr Cl4-trifluoromethoxyphenyl 1973 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1974 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1975 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1976 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1977 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1978 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1979 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1980 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1981 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1982 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1983 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1984 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 1985 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1986CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1987 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-tolyl 1988 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1989cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1990 cyclobutylmethyl H OCH₂ CF₃ OCH₂ CF₃ 4-tolyl 1991 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1992(CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1993 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl1994 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1995 5,5-spiro[2.3]hexane O CH₂CF₃ OCH₂ CF₃ 4-tolyl 1996 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 1997CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 1998 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 1999 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl2000 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2001cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2002cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2003 (CH₂)₂ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 2004 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-ethylphenyl 2005 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2006 (CH₂)₅ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 2007 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-ethyl phenyl 2008 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2009CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2010 CH₂CF₃ H O CH₂ CF₃OCH₂ CF₃ 4-isopropyl phenyl 2011 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-isopropyl phenyl 2012 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropylphenyl 2013 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl2014 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2015(CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2016 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2017 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl2018 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 20195,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2020Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2031 CH₂CH₃ H O CH₂CF₃ OCH₂ CF₃ 4-thiomethylphenyl 2032 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2033 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2034 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2035 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2036 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2037 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl2038 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 2039 (CH₂)₄ O CH₂ CF₃OCH₂ CF₃ 4-thiomethylphenyl 2040 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2041 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2042 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2043 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2044 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2045 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2046 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2047 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2048 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2049 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2050 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2051 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2052 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2053 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2054 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2055 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2056 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2057 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2058 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2059 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2060 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2061 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2062 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2063 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2064 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2065 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2066 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2067 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2068CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2069 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2070 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2071cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2072 cyclobutylmethyl HO CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2073 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2074(CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2075 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-tolyl 2076 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 20775,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2078 Cyclopentyl H OCH₂-c-Pr OCH₂ CF₃ 4-tolyl 2079 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 2080 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2081 CH₂CH₂CH₃ HO CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2082 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 2083 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 2084 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2085(CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2086 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 2087 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2088(CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2089 5,5-spiro[2.3]hexane OCH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2090 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-ethyl phenyl 2091 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2092CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2093 CH₂CH₂CH₃ H OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2094 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl phenyl 2095 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2096 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2097 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl2098 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2099 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2100 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2101 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2102 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃ 4-isopropylphenyl 2103 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2104 CH₂CF₃H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2105 CH₂CH₂CH₃ H O CH₂-c-PrOCH₂ CF₃ 4-thiomethylphenyl 2106 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2107 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2108 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2109 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl2110 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2111 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2112 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2113 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2114 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2115 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2116 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2117 CH2CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2118 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2119 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2120 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2121 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2122 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2123 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2124 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2125 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2126 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl

TABLE 7 Compounds of Formula VII Ex R1 R2 Y R4 R5 Z 2127 CH₂CH₃ H O CH₂CF₃ CF₃ 4-trifluoromethylphenyl 2128 CH₂CF₃ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2129 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2130 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2131 cyclopropylmethyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2132 cyclobutylmethyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2133 (CH₂)₂ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2134 (CH₂)₃ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2135 (CH₂)₄ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2136 (CH₂)₅ O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2137 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2138 Cyclopentyl H O CH₂ CF₃ CF₃4-trifluoromethylphenyl 2139 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl 2140 CH₂CF₃H O CH₂ CF₃ CF₃ 4-tolyl 2141 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-tolyl 2142CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-tolyl 2143 cyclopropylmethyl H O CH₂ CF₃CF₃ 4-tolyl 2144 cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-tolyl 2145 (CH₂)₂ OCH₂ CF₃ CF₃ 4-tolyl 2146 (CH₂)₃ O CH₂ CF₃ CF₃ 4-tolyl 2147 (CH₂)₄ O CH₂CF₃ CF₃ 4-tolyl 2148 (CH₂)₅ O CH₂ CF₃ CF₃ 4-tolyl 21495,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-tolyl 2150 Cyclopentyl H O CH₂ CF₃CF₃ 4-tolyl 2151 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 2152 CH₂CF₃ H OCH₂ CF₃ CF₃ 4-ethyl phenyl 2153 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-ethyl phenyl2154 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-ethyl phenyl 2155 cyclopropylmethyl HO CH₂ CF₃ CF₃ 4-ethyl phenyl 2156 cyclobutylmethyl H O CH₂ CF₃ CF₃4-ethyl phenyl 2157 (CH₂)₂ O CH₂ CF₃ CF₃ 4-ethyl phenyl 2158 (CH₂)₃ OCH₂ CF₃ CF₃ 4-ethyl phenyl 2159 (CH₂)₄ O CH₂ CF₃ CF₃ 4-ethyl phenyl 2160(CH₂)₅ O CH₂ CF₃ CF₃ 4-ethyl phenyl 2161 5,5-spiro[2.3]hexane O CH₂ CF₃CF₃ 4-ethyl phenyl 2162 Cyclopentyl H O CH₂ CF₃ CF₃ 4-ethyl phenyl 2163CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 2164 CH₂CF₃ H O CH₂ CF₃ CF₃4-isopropyl phenyl 2165 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl2166 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 2167cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 2168cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 2169 (CH₂)₂ O CH₂CF₃ CF₃ 4-isopropyl phenyl 2170 (CH₂)₃ O CH₂ CF₃ CF₃ 4-isopropyl phenyl2171 (CH₂)₄ O CH₂ CF₃ CF₃ 4-isopropyl phenyl 2172 (CH₂)₅ O CH₂ CF₃ CF₃4-isopropyl phenyl 2173 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃ 4-isopropylphenyl 2174 Cyclopentyl H O CH₂ CF₃ CF₃ 4-isopropyl phenyl 2175 CH₂CH₃ HO CH₂ CF₃ CF₃ 4-thiomethylphenyl 2176 CH₂CF₃ H O CH₂ CF₃ CF₃4-thiomethylphenyl 2177 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl2178 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 2179cyclopropylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 2180cyclobutylmethyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl 2181 (CH₂)₂ O CH₂CF₃ CF₃ 4-thiomethylphenyl 2182 (CH₂)₃ O CH₂ CF₃ CF₃ 4-thiomethylphenyl2183 (CH₂)₄ O CH₂ CF₃ CF₃ 4-thiomethylphenyl 2184 (CH₂)₅ O CH₂ CF₃ CF₃4-thiomethylphenyl 2185 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-thiomethylphenyl 2186 Cyclopentyl H O CH₂ CF₃ CF₃ 4-thiomethylphenyl2187 CH₂CH₃ H O CH₂ CF₃ CF₃ 4-trifluoromethoxyphenyl 2188 CH₂CF₃ H O CH₂CF₃ CF₃ 4-trifluoromethoxyphenyl 2189 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2190 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2191 cyclopropylmethyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2192 cyclobutylmethyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2193 (CH₂)₂ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2194 (CH₂)₃ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2195 (CH₂)₄ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2196 (CH₂)₅ O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2197 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2198 Cyclopentyl H O CH₂ CF₃ CF₃4-trifluoromethoxyphenyl 2199 CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2200 CH₂CF₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2201 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2202 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2203 cyclopropylmethyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2204 cyclobutylmethyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2205 (CH₂)₂ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2206 (CH₂)₃ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2207 (CH₂)₄ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2208 (CH₂)₅ O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2209 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2210 Cyclopentyl H O CH₂-c-Pr CF₃4-trifluoromethylphenyl 2211 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 2212 CH₂CF₃H O CH₂-c-Pr CF₃ 4-tolyl 2213 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃ 4-tolyl 2214CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-tolyl 2215 cyclopropylmethyl H O CH₂-c-PrCF₃ 4-tolyl 2216 cyclobutylmethyl H O CH₂-c-Pr CF₃ 4-tolyl 2217 (CH₂)₂ OCH₂-c-Pr CF₃ 4-tolyl 2218 (CH₂)₃ O CH₂-c-Pr CF₃ 4-tolyl 2219 (CH₂)₄ OCH₂-c-Pr CF₃ 4-tolyl 2220 (CH₂)₅ O CH₂-c-Pr CF₃ 4-tolyl 22215,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-tolyl 2222 Cyclopentyl H OCH₂-c-Pr CF₃ 4-tolyl 2223 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 2224CH₂CF₃ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 2225 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-ethyl phenyl 2226 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃ 4-ethyl phenyl 2227cyclopropylmethyl H O CH₂-c-Pr CF₃ 4-ethyl phenyl 2228 cyclobutylmethylH O CH₂-c-Pr CF₃ 4-ethyl phenyl 2229 (CH₂)₂ O CH₂-c-Pr CF₃ 4-ethylphenyl 2230 (CH₂)₃ O CH₂-c-Pr CF₃ 4-ethyl phenyl 2231 (CH₂)₄ O CH₂-c-PrCF₃ 4-ethyl phenyl 2232 (CH₂)₅ O CH₂-c-Pr CF₃ 4-ethyl phenyl 22335,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-ethyl phenyl 2234 Cyclopentyl H OCH₂-c-Pr CF₃ 4-ethyl phenyl 2235 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-isopropylphenyl 2236 CH₂CF₃ H O CH₂-c-Pr CF₃ 4-isopropyl phenyl 2237 CH₂CH₂CH₃ HO CH₂-c-Pr CF₃ 4-isopropyl phenyl 2238 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-isopropyl phenyl 2239 cyclopropylmethyl H O CH₂-c-Pr CF₃ 4-isopropylphenyl 2240 cyclobutylmethyl H O CH₂-c-Pr CF₃ 4-isopropyl phenyl 2241(CH₂)₂ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 2242 (CH₂)₃ O CH₂-c-Pr CF₃4-isopropyl phenyl 2243 (CH₂)₄ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 2244(CH₂)₅ O CH₂-c-Pr CF₃ 4-isopropyl phenyl 2245 5,5-spiro[2.3]hexane OCH₂-c-Pr CF₃ 4-isopropyl phenyl 2246 Cyclopentyl H O CH₂-c-Pr CF₃4-isopropyl phenyl 2247 CH₂CH₃ H O CH₂-c-Pr CF₃ 4-thiomethylphenyl 2248CH₂CF₃ H O CH₂-c-Pr CF₃ 4-thiomethylphenyl 2249 CH₂CH₂CH₃ H O CH₂-c-PrCF₃ 4-thiomethylphenyl 2250 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-thiomethylphenyl 2251 cyclopropylmethyl H O CH₂-c-Pr CF₃4-thiomethylphenyl 2252 cyclobutylmethyl H O CH₂-c-Pr CF₃4-thiomethylphenyl 2253 (CH₂)₂ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 2254(CH₂)₃ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 2255 (CH₂)₄ O CH₂-c-Pr CF₃4-thiomethylphenyl 2256 (CH₂)₅ O CH₂-c-Pr CF₃ 4-thiomethylphenyl 22575,5-spiro[2.3]hexane O CH₂-c-Pr CF₃ 4-thiomethylphenyl 2258 CyclopentylH O CH₂-c-Pr CF₃ 4-thiomethylphenyl 2259 CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2260 CH₂CF₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2261 CH₂CH₂CH₃ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2262 CH₂CH(CH₃)₂ H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2263 cyclopropylmethyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2264 cyclobutylmethyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2265 (CH₂)₂ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2266 (CH₂)₃ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2267 (CH₂)₄ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2268 (CH₂)₅ O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2269 5,5-spiro[2.3]hexane O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2270 Cyclopentyl H O CH₂-c-Pr CF₃4-trifluoromethoxyphenyl 2271 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2272 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2273 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2274 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2275 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2276 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2277 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2278 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2279 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2280 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2281 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2282 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethylphenyl 2283 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2284CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2285 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-tolyl 2286 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2287cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2288 cyclobutylmethyl H OCH₂ CF₃ OCH₂ CF₃ 4-tolyl 2289 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2290(CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2291 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl2292 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2293 5,5-spiro[2.3]hexane O CH₂CF₃ OCH₂ CF₃ 4-tolyl 2294 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-tolyl 2295CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2296 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 2297 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl2298 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2299cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2300cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2301 (CH₂)₂ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 2302 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-ethylphenyl 2303 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2304 (CH₂)₅ O CH₂CF₃ OCH₂ CF₃ 4-ethyl phenyl 2305 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-ethyl phenyl 2306 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-ethyl phenyl 2307CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2308 CH₂CF₃ H O CH₂ CF₃OCH₂ CF₃ 4-isopropyl phenyl 2309 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-isopropyl phenyl 2310 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃ 4-isopropylphenyl 2311 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl2312 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2313(CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2314 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2315 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl2316 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 23175,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2318Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃ 4-isopropyl phenyl 2319 CH₂CH₃ H O CH₂CF₃ OCH₂ CF₃ 4-thiomethylphenyl 2320 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2321 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2322 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2323 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2324 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2325 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl2326 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃ 4-thiomethylphenyl 2327 (CH₂)₄ O CH₂ CF₃OCH₂ CF₃ 4-thiomethylphenyl 2328 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2329 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2330 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-thiomethylphenyl 2331 CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2332 CH₂CF₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2333 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2334 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2335 cyclopropylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2336 cyclobutylmethyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2337 (CH₂)₂ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2338 (CH₂)₃ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2339 (CH₂)₄ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2340 (CH₂)₅ O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2341 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2342 Cyclopentyl H O CH₂ CF₃ OCH₂ CF₃4-trifluoromethoxyphenyl 2343 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2344 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2345 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2346 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2347 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2348 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2349 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2350 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2351 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2352 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2353 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2354 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethylphenyl 2355 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2356CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2357 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂CF₃ 4-tolyl 2358 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2359cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2360 cyclobutylmethyl HO CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2361 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2362(CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2363 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-tolyl 2364 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 23655,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃ 4-tolyl 2366 Cyclopentyl H OCH₂-c-Pr OCH₂ CF₃ 4-tolyl 2367 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 2368 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2369 CH₂CH₂CH₃ HO CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2370 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 2371 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethylphenyl 2372 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2373(CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2374 (CH₂)₃ O CH₂-c-Pr OCH₂CF₃ 4-ethyl phenyl 2375 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2376(CH₂)₅ O CH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2377 5,5-spiro[2.3]hexane OCH₂-c-Pr OCH₂ CF₃ 4-ethyl phenyl 2378 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-ethyl phenyl 2379 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2380CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2381 CH₂CH₂CH₃ H OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2382 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂CF₃ 4-isopropyl phenyl 2383 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2384 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2385 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl2386 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2387 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-isopropyl phenyl 2388 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2389 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-isopropyl phenyl 2390 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃ 4-isopropylphenyl 2391 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2392 CH₂CF₃H O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2393 CH₂CH₂CH₃ H O CH₂-c-PrOCH₂ CF₃ 4-thiomethylphenyl 2394 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2395 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2396 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2397 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl2398 (CH₂)₃ O CH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2399 (CH₂)₄ OCH₂-c-Pr OCH₂ CF₃ 4-thiomethylphenyl 2400 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2401 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2402 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-thiomethylphenyl 2403 CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2404 CH₂CF₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2405 CH₂CH₂CH₃ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2406 CH₂CH(CH₃)₂ H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2407 cyclopropylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2408 cyclobutylmethyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2409 (CH₂)₂ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2410 (CH₂)3 O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2411 (CH₂)₄ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2412 (CH₂)₅ O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2413 5,5-spiro[2.3]hexane O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl 2414 Cyclopentyl H O CH₂-c-Pr OCH₂ CF₃4-trifluoromethoxyphenyl

TABLE 8 Compounds of Formula VII Ex R1 R2 Y R4 R5 Z 2415 CH₂CH₃ H O CH₂CF₃ Cl 4-trifluoromethylphenyl 2416 CH₂CF₃ H O CH₂ CF₃ Cl4-trifluoromethylphenyl 2417 CH₂CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethylphenyl 2418 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-trifluoromethylphenyl 2419 cyclopropylmethyl H O CH₂ CF₃ Cl4-trifluoromethylphenyl 2420 cyclobutylmethyl H O CH₂ CF₃ Cl4-trifluoromethylphenyl 2421 (CH₂)₂ O CH₂ CF₃ Cl 4-trifluoromethylphenyl2422 (CH₂)₃ O CH₂ CF₃ Cl 4-trifluoromethylphenyl 2423 (CH₂)₄ O CH₂ CF₃Cl 4-trifluoromethylphenyl 2424 (CH₂)₅ O CH₂ CF₃ Cl4-trifluoromethylphenyl 2425 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl4-trifluoromethylphenyl 2426 Cyclopentyl H O CH₂ CF₃ Cl4-trifluoromethylphenyl 2427 CH₂CH₃ H O CH₂ CF₃ Cl 4-tolyl 2428 CH₂CF₃ HO CH₂ CF₃ Cl 4-tolyl 2429 CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-tolyl 2430CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-tolyl 2431 cyclopropylmethyl H O CH₂ CF₃ Cl4-tolyl 2432 cyclobutylmethyl H O CH₂ CF₃ Cl 4-tolyl 2433 (CH₂)₂ O CH₂CF₃ Cl 4-tolyl 2434 (CH₂)₃ O CH₂ CF₃ Cl 4-tolyl 2435 (CH₂)₄ O CH₂ CF₃ Cl4-tolyl 2436 (CH₂)₅ O CH₂ CF₃ Cl 4-tolyl 2437 5,5-spiro[2.3]hexane O CH₂CF₃ Cl 4-tolyl 2438 Cyclopentyl H O CH₂ CF₃ Cl 4-tolyl 2439 CH₂CH₃ H OCH₂ CF₃ Cl 4-ethyl phenyl 2440 CH₂CF₃ H O CH₂ CF₃ Cl 4-ethyl phenyl 2441CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-ethyl phenyl 2442 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-ethyl phenyl 2443 cyclopropylmethyl H O CH₂ CF₃ Cl 4-ethyl phenyl 2444cyclobutylmethyl H O CH₂ CF₃ Cl 4-ethyl phenyl 2445 (CH₂)₂ O CH₂ CF₃ Cl4-ethyl phenyl 2446 (CH₂)₃ O CH₂ CF₃ Cl 4-ethyl phenyl 2447 (CH₂)₄ O CH₂CF₃ Cl 4-ethyl phenyl 2448 (CH₂)₅ O CH₂ CF₃ Cl 4-ethyl phenyl 24495,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-ethyl phenyl 2450 Cyclopentyl H OCH₂ CF₃ Cl 4-ethyl phenyl 2451 CH₂CH₃ H O CH₂ CF₃ Cl 4-isopropyl phenyl2452 CH₂CF₃ H O CH₂ CF₃ Cl 4-isopropyl phenyl 2453 CH₂CH₂CH₃ H O CH₂ CF₃Cl 4-isopropyl phenyl 2454 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-isopropyl phenyl2455 cyclopropylmethyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 2456cyclobutylmethyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 2457 (CH₂)₂ O CH₂ CF₃Cl 4-isopropyl phenyl 2458 (CH₂)₃ O CH₂ CF₃ Cl 4-isopropyl phenyl 2459(CH₂)₄ O CH₂ CF₃ Cl 4-isopropyl phenyl 2460 (CH₂)₅ O CH₂ CF₃ Cl4-isopropyl phenyl 2461 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-isopropylphenyl 2462 Cyclopentyl H O CH₂ CF₃ Cl 4-isopropyl phenyl 2463 CH₂CH₃ HO CH₂ CF₃ Cl 4-thiomethylphenyl 2464 CH₂CF₃ H O CH₂ CF₃ Cl4-thiomethylphenyl 2465 CH₂CH₂CH₃ H O CH₂ CF₃ Cl 4-thiomethylphenyl 2466CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl 4-thiomethylphenyl 2467 cyclopropylmethyl H OCH₂ CF₃ Cl 4-thiomethylphenyl 2468 cyclobutylmethyl H O CH₂ CF₃ Cl4-thiomethylphenyl 2469 (CH₂)₂ O CH₂ CF₃ Cl 4-thiomethylphenyl 2470(CH₂)₃ O CH₂ CF₃ Cl 4-thiomethylphenyl 2471 (CH₂)₄ O CH₂ CF₃ Cl4-thiomethylphenyl 2472 (CH₂)₅ O CH₂ CF₃ Cl 4-thiomethylphenyl 24735,5-spiro[2.3]hexane O CH₂ CF₃ Cl 4-thiomethylphenyl 2474 Cyclopentyl HO CH₂ CF₃ Cl 4-thiomethylphenyl 2475 CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2476 CH₂CF₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2477 CH₂CH₂CH₃ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2478 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2479 cyclopropylmethyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2480 cyclobutylmethyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2481 (CH₂)₂ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2482 (CH₂)₃ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2483 (CH₂)₄ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2484 (CH₂)₅ O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2485 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2486 Cyclopentyl H O CH₂ CF₃ Cl4-trifluoromethoxyphenyl 2487 CH₂CH₃ H O CH₂—c-Pr Cl4-trifluoromethylphenyl 2488 CH₂CF₃ H O CH₂—c-Pr Cl4-trifluoromethylphenyl 2489 CH₂CH₂CH₃ H O CH₂—c-Pr Cl4-trifluoromethylphenyl 2490 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl4-trifluoromethylphenyl 2491 cyclopropylmethyl H O CH₂—c-Pr Cl4-trifluoromethylphenyl 2492 cyclobutylmethyl H O CH₂—c-Pr Cl4-trifluoromethylphenyl 2493 (CH₂)₂ O CH₂—c-Pr Cl4-trifluoromethylphenyl 2494 (CH₂)₃ O CH₂—c-Pr Cl4-trifluoromethylphenyl 2495 (CH₂)₄ O CH₂—c-Pr Cl4-trifluoromethylphenyl 2496 (CH₂)₅ O CH₂—c-Pr Cl4-trifluoromethylphenyl 2497 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl4-trifluoromethylphenyl 2498 Cyclopentyl H O CH₂—c-Pr Cl4-trifluoromethylphenyl 2499 CH₂CH₃ H O CH₂—c-Pr Cl 4-tolyl 2500 CH₂CF₃H O CH₂—c-Pr Cl 4-tolyl 2501 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-tolyl 2502CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-tolyl 2503 cyclopropylmethyl H O CH₂—c-PrCl 4-tolyl 2504 cyclobutylmethyl H O CH₂—c-Pr Cl 4-tolyl 2505 (CH₂)₂ OCH₂—c-Pr Cl 4-tolyl 2506 (CH₂)₃ O CH₂—c-Pr Cl 4-tolyl 2507 (CH₂)₄ OCH₂—c-Pr Cl 4-tolyl 2508 (CH₂)₅ O CH₂—c-Pr Cl 4-tolyl 25095,5-spiro[2.3]hexane O CH₂—c-Pr Cl 4-tolyl 2510 Cyclopentyl H O CH₂—c-PrCl 4-tolyl 2511 CH₂CH₃ H O CH₂—c-Pr Cl 4-ethyl phenyl 2512 CH₂CF₃ H OCH₂—c-Pr Cl 4-ethyl phenyl 2513 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-ethyl phenyl2514 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-ethyl phenyl 2515 cyclopropylmethyl HO CH₂—c-Pr Cl 4-ethyl phenyl 2516 cyclobutylmethyl H O CH₂—c-Pr Cl4-ethyl phenyl 2517 (CH₂)₂ O CH₂—c-Pr Cl 4-ethyl phenyl 2518 (CH₂)₃ OCH₂—c-Pr Cl 4-ethyl phenyl 2519 (CH₂)₄ O CH₂—c-Pr Cl 4-ethyl phenyl 2520(CH₂)₅ O CH₂—c-Pr Cl 4-ethyl phenyl 2521 5,5-spiro[2.3]hexane O CH₂—c-PrCl 4-ethyl phenyl 2522 Cyclopentyl H O CH₂—c-Pr Cl 4-ethyl phenyl 2523CH₂CH₃ H O CH₂—c-Pr Cl 4-isopropyl phenyl 2524 CH₂CF₃ H O CH₂—c-Pr Cl4-isopropyl phenyl 2525 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-isopropyl phenyl2526 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-isopropyl phenyl 2527cyclopropylmethyl H O CH₂—c-Pr Cl 4-isopropyl phenyl 2528cyclobutylmethyl H O CH₂—c-Pr Cl 4-isopropyl phenyl 2529 (CH₂)₂ OCH₂—c-Pr Cl 4-isopropyl phenyl 2530 (CH₂)₃ O CH₂—c-Pr Cl 4-isopropylphenyl 2531 (CH₂)₄ O CH₂—c-Pr Cl 4-isopropyl phenyl 2532 (CH₂)₅ OCH₂—c-Pr Cl 4-isopropyl phenyl 2533 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl4-isopropyl phenyl 2534 Cyclopentyl H O CH₂—c-Pr Cl 4-isopropyl phenyl2535 CH₂CH₃ H O CH₂—c-Pr Cl 4-thiomethylphenyl 2536 CH₂CF₃ H O CH₂—c-PrCl 4-thiomethylphenyl 2537 CH₂CH₂CH₃ H O CH₂—c-Pr Cl 4-thiomethylphenyl2538 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl 4-thiomethylphenyl 2539cyclopropylmethyl H O CH₂—c-Pr Cl 4-thiomethylphenyl 2540cyclobutylmethyl H O CH₂—c-Pr Cl 4-thiomethylphenyl 2541 (CH₂)₂ OCH₂—c-Pr Cl 4-thiomethylphenyl 2542 (CH₂)₃ O CH₂—c-Pr Cl4-thiomethylphenyl 2543 (CH₂)₄ O CH₂—c-Pr Cl 4-thiomethylphenyl 2544(CH₂)₅ O CH₂—c-Pr Cl 4-thiomethylphenyl 2545 5,5-spiro[2.3]hexane OCH₂—c-Pr Cl 4-thiomethylphenyl 2546 Cyclopentyl H O CH₂—c-Pr Cl4-thiomethylphenyl 2547 CH₂CH₃ H O CH₂—c-Pr Cl 4-trifluoromethoxyphenyl2548 CH₂CF₃ H O CH₂—c-Pr Cl 4-trifluoromethoxyphenyl 2549 CH₂CH₂CH₃ H OCH₂—c-Pr Cl 4-trifluoromethoxyphenyl 2550 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2551 cyclopropylmethyl H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2552 cyclobutylmethyl H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2553 (CH₂)₂ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2554 (CH₂)₃ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2555 (CH₂)₄ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2556 (CH₂)₅ O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2557 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2558 Cyclopentyl H O CH₂—c-Pr Cl4-trifluoromethoxyphenyl 2559 CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2560 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2561 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2562 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2563 cyclopropylmethyl H O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2564 cyclobutylmethyl H O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2565 (CH₂)₂ O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2566 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2567 (CH₂)₄ O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2568 (CH₂)₅ O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2569 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2570 Cyclopentyl H O CH₂ CF₃ OCH₂CF₃4-trifluoromethylphenyl 2571 CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2572CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2573 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃4-tolyl 2574 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2575cyclopropylmethyl H O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2576 cyclobutylmethyl H OCH₂ CF₃ OCH₂CF₃ 4-tolyl 2577 (CH₂)₂ O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2578(CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2579 (CH₂)₄ O CH₂ CF₃ OCH₂CF₃ 4-tolyl2580 (CH₂)₅ O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2581 5,5-spiro[2.3]hexane O CH₂CF₃ OCH₂CF₃ 4-tolyl 2582 Cyclopentyl H O CH₂ CF₃ OCH₂CF₃ 4-tolyl 2583CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 2584 CH₂CF₃ H O CH₂ CF₃OCH₂CF₃ 4-ethyl phenyl 2585 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl2586 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 2587cyclopropylmethyl H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 2588cyclobutylmethyl H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 2589 (CH₂)₂ O CH₂CF₃ OCH₂CF₃ 4-ethyl phenyl 2590 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl2591 (CH₂)₄ O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 2592 (CH₂)₅ O CH₂ CF₃OCH₂CF₃ 4-ethyl phenyl 2593 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂CF₃4-ethyl phenyl 2594 Cyclopentyl H O CH₂ CF₃ OCH₂CF₃ 4-ethyl phenyl 2595CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2596 CH₂CF₃ H O CH₂ CF₃OCH₂CF₃ 4-isopropyl phenyl 2597 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃4-isopropyl phenyl 2598 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂CF₃ 4-isopropylphenyl 2599 cyclopropylmethyl H O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl2600 cyclobutylmethyl H O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2601 (CH₂)₂O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2602 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃4-isopropyl phenyl 2603 (CH₂)₄ O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2604(CH₂)₅ O CH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2605 5,5-spiro[2.3]hexane OCH₂ CF₃ OCH₂CF₃ 4-isopropyl phenyl 2606 Cyclopentyl H O CH₂ CF₃ OCH₂CF₃4-isopropyl phenyl 2607 CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃ 4-thiomethylphenyl2608 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃ 4-thiomethylphenyl 2609 CH₂CH₂CH₃ H OCH₂ CF₃ OCH₂CF₃ 4-thiomethylphenyl 2610 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂CF₃4-thiomethylphenyl 2611 cyclopropylmethyl H O CH₂ CF₃ OCH₂CF₃4-thiomethylphenyl 2612 cyclobutylmethyl H O CH₂ CF₃ OCH₂CF₃4-thiomethylphenyl 2613 (CH₂)₂ O CH₂ CF₃ OCH₂CF₃ 4-thiomethylphenyl 2614(CH₂)₃ O CH₂ CF₃ OCH₂CF₃ 4-thiomethylphenyl 2615 (CH₂)₄ O CH₂ CF₃OCH₂CF₃ 4-thiomethylphenyl 2616 (CH₂)₅ O CH₂ CF₃ OCH₂CF₃4-thiomethylphenyl 2617 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂CF₃4-thiomethylphenyl 2618 Cyclopentyl H O CH₂ CF₃ OCH₂CF₃4-thiomethylphenyl 2619 CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2620 CH₂CF₃ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2621 CH₂CH₂CH₃ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2622 CH₂CH(CH₃)₂ H O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2623 cyclopropylmethyl H O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2624 cyclobutylmethyl H O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2625 (CH₂)₂ O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2626 (CH₂)₃ O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2627 (CH₂)₄ O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2628 (CH₂)₅ O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2629 5,5-spiro[2.3]hexane O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2630 Cyclopentyl H O CH₂ CF₃ OCH₂CF₃4-trifluoromethoxyphenyl 2632 CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2633 CH₂CF₃ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2634 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2635 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2636 cyclopropylmethyl H O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2637 cyclobutylmethyl H O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2638 (CH₂)₂ O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2639 (CH₂)₃ O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2640 (CH₂)₄ O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2641 (CH₂)₅ O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2642 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2643 Cyclopentyl H O CH₂—c-Pr OCH₂CF₃4-trifluoromethylphenyl 2644 CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃ 4-tolyl 2645CH₂CF₃ H O CH₂—c-Pr OCH₂CF₃ 4-tolyl 2646 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃4-tolyl 2647 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃ 4-tolyl 2648cyclopropylmethyl H O CH₂—c-Pr OCH₂CF₃ 4-tolyl 2649 cyclobutylmethyl H OCH₂—c-Pr OCH₂CF₃ 4-tolyl 2650 (CH₂)₂ O CH₂—c-Pr OCH₂CF₃ 4-tolyl 2651(CH₂)₃ O CH₂—c-Pr OCH₂CF₃ 4-tolyl 2652 (CH₂)₄ O CH₂—c-Pr OCH₂CF₃ 4-tolyl2653 (CH₂)₅ O CH₂—c-Pr OCH₂CF₃ 4-tolyl 2654 5,5-spiro[2.3]hexane OCH₂—c-Pr OCH₂CF₃ 4-tolyl 2655 Cyclopentyl H O CH₂—c-Pr OCH₂CF₃ 4-tolyl2656 CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 2657 CH₂CF₃ H O CH₂—c-PrOCH₂CF₃ 4-ethyl phenyl 2658 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃ 4-ethylphenyl 2659 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 2660cyclopropylmethyl H O CH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 2661cyclobutylmethyl H O CH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 2662 (CH₂)₂ OCH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 2663 (CH₂)₃ O CH₂—c-Pr OCH₂CF₃ 4-ethylphenyl 2664 (CH₂)₄ O CH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 2665 (CH₂)₅ OCH₂—c-Pr OCH₂CF₃ 4-ethyl phenyl 2666 5,5-spiro[2.3]hexane O CH₂—c-PrOCH₂CF₃ 4-ethyl phenyl 2667 Cyclopentyl H O CH₂—c-Pr OCH₂CF₃ 4-ethylphenyl 2668 CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃ 4-isopropyl phenyl 2669 CH₂CF₃ HO CH₂—c-Pr OCH₂CF₃ 4-isopropyl phenyl 2670 CH₂CH₂CH₃ H O CH₂—c-PrOCH₂CF₃ 4-isopropyl phenyl 2671 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃4-isopropyl phenyl 2672 cyclopropylmethyl H O CH₂—c-Pr OCH₂CF₃4-isopropyl phenyl 2673 cyclobutylmethyl H O CH₂—c-Pr OCH₂CF₃4-isopropyl phenyl 2674 (CH₂)₂ O CH₂—c-Pr OCH₂CF₃ 4-isopropyl phenyl2675 (CH₂)₃ O CH₂—c-Pr OCH₂CF₃ 4-isopropyl phenyl 2676 (CH₂)₄ O CH₂—c-PrOCH₂CF₃ 4-isopropyl phenyl 2677 (CH₂)₅ O CH₂—c-Pr OCH₂CF₃ 4-isopropylphenyl 2678 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂CF₃ 4-isopropyl phenyl2679 Cyclopentyl H O CH₂—c-Pr OCH₂CF₃ 4-isopropyl phenyl 2680 CH₂CH₃ H OCH₂—c-Pr OCH₂CF₃ 4-thiomethylphenyl 2681 CH₂CF₃ H O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2682 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2683 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2684 cyclopropylmethyl H O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2685 cyclobutylmethyl H O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2686 (CH₂)₂ O CH₂—c-Pr OCH₂CF₃ 4-thiomethylphenyl2687 (CH₂)₃ O CH₂—c-Pr OCH₂CF₃ 4-thiomethylphenyl 2688 (CH₂)₄ O CH₂—c-PrOCH₂CF₃ 4-thiomethylphenyl 2689 (CH₂)₅ O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2690 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2691 Cyclopentyl H O CH₂—c-Pr OCH₂CF₃4-thiomethylphenyl 2692 CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2693 CH₂CF₃ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2694 CH₂CH₂CH₃ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2695 CH₂CH(CH₃)₂ H O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2696 cyclopropylmethyl H O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2697 cyclobutylmethyl H O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2698 (CH₂)₂ O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2699 (CH₂)₃ O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2700 (CH₂)₄ O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2701 (CH₂)₅ O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2702 5,5-spiro[2.3]hexane O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl 2703 Cyclopentyl H O CH₂—c-Pr OCH₂CF₃4-trifluoromethoxyphenyl

TABLE 9 Compounds of Formula III Ex R1 R2 Y R4 R5 Z 2704 CH₂CH₃ H O CH₂CH₂ CF₃ Cl 4-trifluoromethylphenyl 2705 CH₂CF₃ H O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2706 CH₂CH₂CH₃ H O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2707 CH₂CH(CH₃)₂ H O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2708 cyclopropylmethyl H O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2709 cyclobutylmethyl H O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2710 (CH₂)₂ O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2711 (CH₂)₃ O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2712 (CH₂)₄ O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2713 (CH₂)₅ O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2714 5,5-spiro[2.3]hexane O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl 2715 Cyclopentyl H O CH₂ CH₂ CF₃ Cl4-trifluoromethylphenyl

TABLE 10 Compounds of Formula III Ex R1 R2 Y R4 R5 Z 2716 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c][1,2,5]oxadiazole 2717 CH₂CF₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2718 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2719 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2720 cyclopropylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2721 cyclobutylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2722 (CH₂)₂ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2723 (CH₂)₃ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2724 (CH₂)₄ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2725 (CH₂)₅ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2726 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2727 Cyclopentyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2733 cyclobutylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2735 (CH₂)₃ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2737 (CH₂)₅ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2738 5,5-spiro[2.3]hexane O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2739 Cyclopentyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2745 cyclobutylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2747 (CH₂)₃ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2749 (CH₂)₅ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2750 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2751 Cyclopentyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2752 CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2753 CH₂CF₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2754 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2755 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2756 cyclopropylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2757 cyclobutylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2758 (CH₂)₂ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2759 (CH₂)₃ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2760 (CH₂)₄ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2761 (CH₂)₅ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2762 5,5-spiro[2.30]hexane O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2763 Cyclopentyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2769 cyclobutylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2771 (CH₂)₃ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2773 (CH₂)₅ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2774 5,5-spiro[2.3]hexane O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2775 Cyclopentyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2781 cyclobutylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2783 (CH₂)₃ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2785 (CH₂)₅ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2786 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2787 Cyclopentyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2788 CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2789 CH₂CF₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2790 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2791 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2792 cyclopropylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2793 cyclobutylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2794 (CH₂)₂ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2795 (CH₂)₃ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2796 (CH₂)₄ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2797 (CH₂)₅ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2798 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2799 Cyclopentyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2805 cyclobutylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2807 (CH₂)₃ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2809 (CH₂)₅ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2810 5,5-spiro[2.3]hexane O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2811 Cyclopentyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2817 cyclobutylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2819 (CH₂)₃ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2821 (CH₂)₅ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2822 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2823 Cyclopentyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2824 CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2825 CH₂CF₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2826 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2827 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2828 cyclopropylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2829 cyclobutylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2830 (CH₂)₂ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2831 (CH₂)₃ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2832 (CH₂)₄ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2833 (CH₂)₅ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2834 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2835 Cyclopentyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2841 cyclobutylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2843 (CH₂)₃ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2845 (CH₂)₅ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2846 5,5-spiro[2.3]hexane O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2847 Cyclopentyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2853 cyclobutylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2855 (CH₂)₃ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2857 (CH₂)₅ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2858 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2859 Cyclopentyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole

TABLE 11 Compounds of Formula IV Ex R1 R2 X R3 R5 Z 2860 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c][1,2,5]oxadiazole 2861 CH₂CF₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2862 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2863 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2864 cyclopropylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2865 cyclobutylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2866 (CH₂)₂ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2867 (CH₂)₃ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2868 (CH₂)₄ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2869 (CH₂)₅ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2870 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2871 Cyclopentyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 2872 CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2873 CH₂CF₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2874 CH₂CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2875 CH₂CH(CH₃)₂ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2876 cyclopropylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2877 cyclobutylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2878 (CH₂)₂ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2879 (CH₂)₃ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2880 (CH₂)₄ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2881 (CH₂)₅ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2882 5,5-spiro[2.3]hexane O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2883 Cyclopentyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 2884 CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2885 CH₂CF₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2886 CH₂CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2887 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2888 cyclopropylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2889 cyclobutylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2890 (CH₂)₂ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2891 (CH₂)₃ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2892 (CH₂)₄ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2893 (CH₂)₅ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2894 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2895 Cyclopentyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 2896 CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2897 CH₂CF₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2898 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2899 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2900 cyclopropylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2901 cyclobutylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2902 (CH₂)₂ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2903 (CH₂)₃ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2904 (CH₂)₄ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2905 (CH₂)₅ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2906 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2907 Cyclopentyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 2908 CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2909 CH₂CF₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2910 CH₂CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2911 CH₂CH(CH₃)₂ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2912 cyclopropylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2913 cyclobutylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2914 (CH₂)₂ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2915 (CH₂)₃ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2916 (CH₂)₄ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2917 (CH₂)₅ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2918 5,5-spiro[2.3]hexane O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2919 Cyclopentyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 2920 CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2921 CH₂CF₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2922 CH₂CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2923 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2924 cyclopropylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2925 cyclobutylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2926 (CH₂)₂ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2927 (CH₂)₃ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2928 (CH₂)₄ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2929 (CH₂)₅ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2930 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2931 Cyclopentyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 2932 CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2933 CH₂CF₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2934 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2935 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2936 cyclopropylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2937 cyclobutylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2938 (CH₂)₂ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2939 (CH₂)₃ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2940 (CH₂)₄ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2941 (CH₂)₅ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2942 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2943 Cyclopentyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 2944 CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2945 CH₂CF₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2946 CH₂CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2947 CH₂CH(CH₃)₂ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2948 cyclopropylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2949 cyclobutylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2950 (CH₂)₂ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2951 (CH₂)₃ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2952 (CH₂)₄ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2953 (CH₂)₅ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2954 5,5-spiro[2.3]hexane O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2955 Cyclopentyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 2956 CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2957 CH₂CF₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2958 CH₂CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2959 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2960 cyclopropylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2961 cyclobutylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2962 (CH₂)₂ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2963 (CH₂)₃ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2964 (CH₂)₄ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2965 (CH₂)₅ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2966 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2967 Cyclopentyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 2968 CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2969 CH₂CF₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2970 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2971 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2972 cyclopropylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2973 cyclobutylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2974 (CH₂)₂ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2975 (CH₂)₃ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2976 (CH₂)₄ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2977 (CH₂)₅ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2978 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2979 Cyclopentyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 2980 CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2981 CH₂CF₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2982 CH₂CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2983 CH₂CH(CH₃)₂ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2984 cyclopropylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2985 cyclobutylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2986 (CH₂)₂ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2987 (CH₂)₃ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2988 (CH₂)₄ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2989 (CH₂)₅ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2990 5,5-spiro[2.3]hexane O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2991 Cyclopentyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 2992 CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2993 CH₂CF₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2994 CH₂CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2995 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2996 cyclopropylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2997 cyclobutylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2998 (CH₂)₂ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 2999 (CH₂)₃ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3000 (CH₂)₄ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3001 (CH₂)₅ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3002 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3003 Cyclopentyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole

TABLE 12 Compounds of Formula VII Ex R1 R2 Y R4 R5 Z 3004 CH₂CH₃ H O CH₂CF₃ CF₃ 5-benzo[c][1,2,5]oxadiazole 3005 CH₂CF₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3006 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3007 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3008 cyclopropylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3009 cyclobutylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3010 (CH₂)₂ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3011 (CH₂)₃ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3012 (CH₂)₄ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3013 (CH₂)₅ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3014 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3015 Cyclopentyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]oxadiazole 3016 CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3017 CH₂CF₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3018 CH₂CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3019 CH₂CH(CH₃)₂ H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3020 cyclopropylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3021 cyclobutylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3022 (CH₂)₂ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3023 (CH₂)₃ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3024 (CH₂)₄ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3025 (CH₂)₅ O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3026 5,5-spiro[2.3]hexane O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3027 Cyclopentyl H O CH₂ CF₃ F5-benzo[c][1,2,5]oxadiazole 3028 CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3029 CH₂CF₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3030 CH₂CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3031 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3032 cyclopropylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3033 cyclobutylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3034 (CH₂)₂ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3035 (CH₂)₃ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3036 (CH₂)₄ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3037 (CH₂)₅ O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3038 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3039 Cyclopentyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]oxadiazole 3040 CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3041 CH₂CF₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3042 CH₂CH₂CH₃ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3043 CH₂CH(CH₃)₂ H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3044 cyclopropylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3045 cyclobutylmethyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3046 (CH₂)₂ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3047 (CH₂)₃ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3048 (CH₂)₄ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3049 (CH₂)₅ O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3050 5,5-spiro[2.3]hexane O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3051 Cyclopentyl H O CH₂ CF₃ CF₃5-benzo[c][1,2,5]thiadiazole 3052 CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3053 CH₂CF₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3054 CH₂CH₂CH₃ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3055 CH₂CH(CH₃)₂ H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3056 cyclopropylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3057 cyclobutylmethyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3058 (CH₂)₂ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3059 (CH₂)₃ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3060 (CH₂)₄ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3061 (CH₂)₅ O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3062 5,5-spiro[2.3]hexane O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3063 Cyclopentyl H O CH₂ CF₃ F5-benzo[c][1,2,5]thiadiazole 3064 CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3065 CH₂CF₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3066 CH₂CH₂CH₃ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3067 CH₂CH(CH₃)₂ H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3068 cyclopropylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3069 cyclobutylmethyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3070 (CH₂)₂ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3071 (CH₂)₃ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3072 (CH₂)₄ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3073 (CH₂)₅ O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3074 5,5-spiro[2.3]hexane O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3075 Cyclopentyl H O CH₂ CF₃ Cl5-benzo[c][1,2,5]thiadiazole 3076 CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3077 CH₂CF₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3078 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3079 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3080 cyclopropylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3081 cyclobutylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3082 (CH₂)₂ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3083 (CH₂)₃ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3084 (CH₂)₄ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3085 (CH₂)₅ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3086 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3087 Cyclopentyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]oxadiazole 3088 CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3089 CH₂CF₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3090 CH₂CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3091 CH₂CH(CH₃)₂ H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3092 cyclopropylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3093 cyclobutylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3094 (CH₂)₂ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3095 (CH₂)₃ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3096 (CH₂)₄ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3097 (CH₂)₅ O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3098 5,5-spiro[2.3]hexane O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3099 Cyclopentyl H O CH₂—c-Pr F5-benzo[c][1,2,5]oxadiazole 3100 CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3101 CH₂CF₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3102 CH₂CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3103 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3104 cyclopropylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3105 cyclobutylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3106 (CH₂)₂ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3107 (CH₂)₃ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3108 (CH₂)₄ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3109 (CH₂)₅ O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3110 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3111 Cyclopentyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]oxadiazole 3112 CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3113 CH₂CF₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3114 CH₂CH₂CH₃ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3115 CH₂CH(CH₃)₂ H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3116 cyclopropylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3117 cyclobutylmethyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3118 (CH₂)₂ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3119 (CH₂)₃ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3120 (CH₂)₄ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3121 (CH₂)₅ O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3122 5,5-spiro[2.3]hexane O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3123 Cyclopentyl H O CH₂—c-Pr CF₃5-benzo[c][1,2,5]thiadiazole 3124 CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3125 CH₂CF₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3126 CH₂CH₂CH₃ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3127 CH₂CH(CH₃)₂ H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3128 cyclopropylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3129 cyclobutylmethyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3130 (CH₂)₂ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3131 (CH₂)₃ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3132 (CH₂)₄ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3133 (CH₂)₅ O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3134 5,5-spiro[2.3]hexane O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3135 Cyclopentyl H O CH₂—c-Pr F5-benzo[c][1,2,5]thiadiazole 3136 CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3137 CH₂CF₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3138 CH₂CH₂CH₃ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3139 CH₂CH(CH₃)₂ H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3140 cyclopropylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3141 cyclobutylmethyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3142 (CH₂)₂ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3143 (CH₂)₃ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3144 (CH₂)₄ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3145 (CH₂)₅ O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3146 5,5-spiro[2.3]hexane O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole 3147 Cyclopentyl H O CH₂—c-Pr Cl5-benzo[c][1,2,5]thiadiazole

Experimental Procedures:

Example 5342-(6-cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step-1

2-(3-Bromo-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)-4-methylpentanoateE-9 (15 g, 63.55 mmol) in 100 ml of glacial acetic acid at 0° C., slowlyadded bromine (20.26 g, 64.14 mol) and stirred at same temperature for2.5 h. After completion the reaction, the reaction mixture was pouredinto water and neutralized with saturated sodium carbonate solution andextracted with ethyl acetate (300 ml×3). The organic layer was washedwith water, saturated sodium bicarbonate solution and brine. The organiclayer was then distilled off to yield product ethyl2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate. Yield: (16 g, 80%). ¹HNMR (CDCl₃): δ 7.20 (m 2H), 6.80 (d, J=7.9 Hz, 1H), 4.90 (bs, 1H), 4.15(q, 2H), 3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50(m, 1H), 1.20 (t, 3H), 1.00 (m, 6H). Mass: (315, M+1, 100%).

Step-2

2-(3-Bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid

Ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (16 g) was taken inacetic acid (100 ml) and to it added drop wise 70% nitric acid (10 ml)below 15° C. The reaction mixture was stirred for 2 h. After completionof the reaction; it was poured into 300 ml of ice water and extractedwith ethyl acetate (300 ml×3). The ethyl acetate layer was washed withbicarbonate solution, water and finally brine solution. The organiclayer was then distilled off and the crude residue was purified bycolumn chromatography using

Ethyl acetate:hexane (2:3) as eluent provided 12 g of2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid. The acid wastaken in 50 ml of absolute ethanol and 2 ml of concentrated sulfuricacid and refluxed for 1 h. The ethanol layer was distilled off, washedit with water and dried gave 13 g of ethyl2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate intermediate. ¹HNMR (CDCl₃): δ 8.20 (s 1H), 7.20 (s, 1H), 4.90 (bs, 1H), 4.15 (q, 2H),3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H),1.20 (t, 3H), 1.00 (m, 6H). Mass: (360, M+1, 100%).

Step 3

Ethyl2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate

A solution of ethyl2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (4.1 g, 11.26mmol) was taken in 50 ml of DMSO and to it added Cs₂CO₃ (3.02 g, 12.39mmol). The reaction mixture was stirred at room temperature for 15minutes and then added cyclopropylmethyl bromide (1.67 g, 12.39 mmol)dropwise. After completion of addition, the reaction mixture was stirredat 70° C. for 4 h. After completion of the reaction, it was poured intowater (200 ml) and extracted with ethyl acetate (100 ml×3). The ethylacetate layer was washed with 1N HCl, water and finally brine solution.The organic layer was then distilled off and the crude residue waspurified by column chromatography using Ethyl acetate:hexane (1:3) aseluent provided 3 g of ethyl2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate. ¹HNMR (CDCl₃): δ 8.20 (s 1H), 7.20 (s, 1H), 4.15 (q, 2H), 3.60 (t, 1H),3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H),1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (414, M+1, 100%).

Step 4

Ethyl2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a solution of ethyl2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate (2g, 4.83 mmol) in 30 ml of DMF/Water (25:5 ml) was added Pd(PPh₃)₄ (558mg, 0.483 mmol), Cs₂CO₃ (5.5 g, 16.9 mmol) and 4-CF3-PhB(OH)₂ (1.01 g,5.31 mmol) and the reaction mixture was stirred at 90° C. for 12 h.After completion of the reaction, it was poured into water (100 ml) andextracted with ethyl acetate (100 ml×3). The ethyl acetate layer waswashed with 1N HCl, water and finally brine solution. The organic layerwas then distilled off and the crude residue was purified by columnchromatography using Ethyl acetate:hexane (2:3) as eluent provided 1.3 gof ethyl2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate.¹H NMR (CDCl₃): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 4.15 (q, 2H), 3.60 (t,1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m,1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (480, M+1,100%).

Step 5

2-(6-(Cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Ethyl2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(100 mg, 0.208 mmol) was taken in a mixture of MeOH; THF:Water (30 ml,10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixturewas stirred at room temperature for 3 h. After completion of thereaction, it was poured into water (50 ml) and extracted with ethylacetate (100 ml×2). The ethyl acetate layer was washed with 1N HCl,water and finally brine solution. The organic layer was then distilledoff and the crude residue was purified by column chromatography usingEthyl acetate:hexane (1:1) as eluent provided 70 mg of2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid. ¹H NMR (CDCl₃): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 3.60 (t, 1H),3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H),1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (452, M+1, 100%).

Example 5542-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(300 mg, 0.626 mmo) was taken in 30 ml of Toluene:Water (1:1) and to itadded Fe powder (203 mg, 3.62 mmol), Ammonium formate (228 mg, 3.62mmol). The reaction mixture was refluxed for 3 h and then filteredthrough celite. The toluene was distilled off under reduced pressure andthe crude residue was purified by column chromatography using Ethylacetate:hexane (2:3) as eluent provided 220 mg of ethyl2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate.¹H NMR (CDCl₃): δ 7.40-7.20 (m, 5H), 6.90 (s 1H), 4.50 (bs, 2H), 4.15(q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m,1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H).Mass: (450, M+1, 100%).

Step 3

2-(5-Amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Ethyl2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate.(120 mg, 0.267 mmol) was taken in a mixture of MeOH; THF:Water (30 ml,10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixturewas stirred at room temperature for 3 h. After completion of thereaction, it was poured into water (50 ml) and extracted with ethylacetate (100 ml x2). The ethyl acetate layer was washed with 1N HCl,water and finally brine solution. The organic layer was then distilledoff and the crude residue was purified by column chromatography usingEthyl acetate:hexane (1:1) as eluent provided 80 mg of2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid. ¹H NMR (CDCl₃): δ 7.40-7.20 (m, 5H), 7.00 (s, 1H), 3.60 (t, 1H),3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H),1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (422, M+1, 100%).

Example 4842-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

2-(6-Cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid (150 mg, 0.33 mmol) was taken up in 10 ml of 6N HCl and a solutionof sodium nitrite (30 mg, 0.40 mmol, 5 ml in water) was added at 0° C.The reaction mixture was stirred for 15 minutes at 0° C. and then pouredinto a saturated solution of copper (II) chloride in water (25 ml) Thereaction mixture was then heated at 70° C. for 3 hours. The mixture wascooled to room temperature and extracted with ethyl acetate (2×100 mL).The combined organic layers were dried (MgSO₄) and concentrated underreduced pressure. The crude residue obtained was purified by columnchromatography using ethyl acetate:hexane (2:3) as eluent to yield 120mg of ethyl2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate.¹H NMR (CDCl₃): δ 7.60-7.45 (m, 5H), 7.20 (s 1H), 4.15 (q, 2H), 3.60 (t,1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m,1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (470, M+1,100%).

Step 2

2-(6-Cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

The ethyl2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoateabove (120 mg, 0.207 mmol) was taken up in a mixture of MeOH; THF:Water(30 ml, 10:10:2) and LiOH (42 mg, 0.7 mmol) was added. The reactionmixture was stirred at room temperature for 3 h. After completion of thereaction, it was poured into water (50 ml) and extracted with ethylacetate (2×100 ml). The combined extracts were washed with 1N HCl, waterand finally brine solution. The combined organic layers were dried(MgSO₄) and concentrated under reduced pressure. The crude residueobtained was purified by column chromatography using ethylacetate:hexane (1:1) as eluent to yield 105 mg of2-(6-cyclopropylmethoxy)-5-chloro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid product. ¹H NMR (CDCl₃): δ 7.65-7.40 (m, 5H), 7.20 (s, 1H), 3.60(t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50(m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (442, M+1, 100%). HPLCPurity (99%).

Example 2642-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid (200 mg, 0.53 mmol) was taken up in 5 ml of 1,2-dichlorobenzene anda solution of BF3-etherate (1.5M, 5 ml) was added at 0° C. The reactionmixture was stirred for 15 minutes at 0° C. and t-butyl nitrite (1.5M, 3ml) was added in a dropwise manner. The reaction mixture was then heatedat 100° C. for 1 hour. The reaction mixture was cooled to roomtemperature and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were dried (MgSO₄) and concentrated under reducedpressure. The crude residue obtained was purified by columnchromatography using ethyl acetate:hexane (2:3) as eluent to provide 120mg of ethyl2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate.¹H NMR (CDCl₃): δ 7.60-7.35 (m, 5H), 7.20 (s 1H), 4.15 (q, 2H), 3.60 (t,1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m,1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (453, M+1,100%).

Step 2

2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

The above ethyl2-(6-cyclopropylmethoxy)-5-amino-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(120 mg, 0.267 mmol) was taken up in MeOH; THF:Water (20 ml, 10:10:2)and LiOH (42 mg, 0.7 mmol) was added. The reaction mixture was stirredat room temperature for 3 h. After completion, the reaction was pouredinto water (50 ml) and extracted with ethyl acetate (2×100 ml). Thecombined ethyl acetate layers were washed with 1N HCl, water and finallybrine solution. The combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure. The crude residue obtained waspurified by column chromatography using ethyl acetate:hexane (1:1) aseluent to yield 85 mg of2-(6-cyclopropylmethoxy)-5-fluoro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid product. ¹H NMR (CDCl₃): δ 7.55-7.30 (m, 5H), 7.10 (s, 1H), 3.60(t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50(m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (425, M+1, 100%). HPLCPurity (97%).

Example 7242-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid

Step 1

Diethyl 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonate

2-Isobutylmalonic acid diethyl ester (40.0 g, 0.185 mol) in DMF (50 mL)was added dropwise to a stirred suspension of sodium hydride (60% inmineral oil, 8.0 g, 0.33 mol) in 200 mL DMF (200 mL) over 20 min. at 0°C. under nitrogen. The mixture was stirred for 0.5 h at roomtemperature, cooled to 0° C. and 1,2,4-trifluoro-5-nitro-benzene (30.0g, 169.5 mmol) in DMF (150 mL) was added dropwise. The resultingreaction mixture was stirred at room temperature for 16 h, poured intoice water (200 mL) and extracted with EtOAc (3×100 mL). The combinedorganic phases were washed with water (3×100 mL), brine (100 mL) anddried (MgSO₄). Evaporation of solvent under reduced pressure gave abrown oil which was purified by column chromatography over silica gel(Heptane-EtOAc, gradient) to give 57.0 g (90%) of2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester asyellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.87 (dd, J=12.3, 6.0 Hz,1H), 7.79 (dd, J=10.1, 6.4 Hz, 1H), 4.30-4.18 (m, 4H), 2.27 (d, J=5.8Hz, 2H), 1.60-1.50 (m, 1H), 1.26 (t, J=7.1 Hz, 6H), 0.82 (d, J=7.0 Hz,6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 168.2, 155.1 (d, ¹J_(CF)=252.3 Hz),150.9 (d, ¹J_(CF)=263.2 Hz), 135.7, 135.1, 120.0 (dd, ²J_(CF)=26.0,³J_(CF)=4.0 Hz), 113.0 (d, ²J_(CF)=29.0 Hz), 62.3, 43.1, 24.9, 23.8,13.8.

Step 2

2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid

The above 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethylester (57.0 g, 152.8 mmol) was dissolved in AcOH/H₂O/EtOH (400 mL/120mL/50 mL) and the reaction mixture was heated under reflux for 96 h.After cooling the solvent was evaporated under reduced pressure andwater (200 mL) was added. The reaction mixture was extracted with EtOAc(3×100 mL), and the combined extracts were washed with water (3×100 mL),brine (100 mL) and dried (MgSO₄). Evaporation of solvent under reducedpressure gave a yellow oil which crystallized on standing to yield 27 gof 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid.Chromatography of the residual oil (Heptane-EtOAc gradient) gave anadditional 3 g of product (72% combined yield). ¹H NMR (300 MHz,CDCl₃/TMS): δ 9.63 (br s, 1H), 7.82 (dd, J=8.8, 6.0 Hz, 1H), 7.38 (dd,J=11.0, 5.8 Hz, 1H), 4.14-4.08 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m,1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS):δ 177.6, 158.2 (d, ¹J_(CF)=232.5 Hz), 150.9 (d, ¹J_(CF)=262.5 Hz),136.0, 134.7, 119.0 (d, ²J_(CF)=20.0, Hz), 113.1 (d, ²J_(CF)=29.4 Hz),41.7, 41.3, 26.0, 22.6, 21.9.

Step 3

2-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester

2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.11mol) was dissolved in EtOH (200 mL) and H₂SO₄ (96%) 10 mL added. Thereaction mixture was refluxed for 3 h and the solvent evaporated to anoil which was dissolved in EtOAc. Water (150 mL) added and the reactionmixture was extracted with EtOAc (3×100 mL). Organic phases washed withsaturated NaHCO₃ (50 mL), water (100 mL) and brine (100 mL) then driedunder MgSO₄. The evaporation of solvent under reduced pressure gave2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester asyellow oil 32.0 g, (97%), which was used for the next step withoutpurification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.81 (dd, J=8.8, 6.2 Hz,1H), 7.41 (dd, J=11.1, 5.6 Hz, 1H), 4.23-4.05 (m, 3H), 2.04-1.94 (m,1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.1 Hz, 3H),0.95-0.92 (m, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 171.6, 155.0 (d,¹J_(CF)=246.0 Hz), 151.5 (d, ¹J_(CF)=261.3 Hz), 145.5, 135.7, 118.8 (dd,²J_(CF)=24.0, ³J_(CF)=4.0 Hz), 113.0 (d, ²J_(CF)=20.0 Hz), 61.6, 41.8,26.1, 22.5, 22.0, 14.1.

Step 4

2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester

Cyclopropylmethanol (10.0 g, 138.8 mmol) was treated with n-BuLi (2.5Min hexane 7.4 g, 46 mL, 115.6 mmol) at −15° C. under nitrogen, and thereaction mixture was stirred 1 h at 25° C. To the mixture was added2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester (29g, 96 mmol) in Cyclopropylmethanol (30 mL) dropwise at 25° C. and thereaction mixture stirred for an additional 16 h. Water (100 mL) wasadded and the reaction mixture was extracted with EtOAc (3×100 mL). Thecombined organic phases washed with water (3×100 mL), brine (100 mL) anddried (MgSO₄). Evaporation of the solvent under reduced pressure gave abrown oil which was purified by column chromatography over silica gel(Heptane-EtOAc gradient) to give 29.5 g, (81%) of2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ7.60 (d, J=9.0 Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 4.07 (t, J=7.7 Hz, 1H),4.00-3.80 (m, 4H), 2.01-1.92 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.43 (m,1H), 1.34-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.65(d, J=7.7 Hz, 2H), 0.54 (d, J=7.7 Hz, 2H), 0.39 (d, J=4.4 Hz, 2H), 0.25(d, J=4.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 172.6, 152.7 (d,¹J_(CF)=243.4 Hz), 148.8, 138.1, 133.3 (d, ²J_(CF)=15.7 Hz), 115.8,112.6 (d, ²J_(CF)=29.5 Hz), 75.1, 70.0, 42.1, 41.7, 26.1, 22.5, 22.2,10.0, 9.8, 3.4.

Step 5

2-(5-Cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester

2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (10.0 g, 26.4 mmol) was dissolved in EtOH (200mL) and hydrogenated at 50 psi, 25° C. for 24 h over 10% Pd—C (1 g). Themixture was filtered and the solvent evaporated to give crude a brownoi, which was purified by column chromatography over silica gel(Heptane-EtOAc gradient) to give 6.7 g, (72%) of2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ6.73 (d, J=6.9 Hz, 1H), 6.40 (d, J=11.0 Hz, 1H), 4.00-3.70 (m, 5H),1.91-1.81 (m, 1H), 1.65-1.56 (m, 1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m,1H), 1.12-1.00 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.63-0.57 (m, 2H),0.53-047 (m, 2H), 0.35-0.28 (m, 2H), 0.25-0.18 (m, 2H); ¹³C NMR (75 MHz,CDCl₃/TMS): δ 174.2, 154.8 (d, ¹J_(CF)=236.0 Hz), 142.6, 136.6 (d,³J_(CF)=11.5 Hz), 114.1 (d, ²J_(CF)=16.8 Hz), 111.6 (d, ³J_(CF)=4.8 Hz),101.6 (d, ²J_(CF)=28.2 Hz), 73.8, 69.2, 42.1, 40.8, 25.9, 22.7, 22.2,10.5, 9.8, 3.2.

Step 6

2-(5-Cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester

2-(5-cyclopropylmethoxy-2-fluoro-4-amino-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (2.9 g, 8.3 mmol) was dissolved in a mixture ofEtOH/H₂O/H₂SO₄ (96%) 50 mL/100 mL/2.5 mL at 0° C. A solution of NaNO₂(0.63 g, 9.1 mmol) in water (20 mL) was added dropwise at 0° C. and thereaction mixture was stirred for 20 min. A solution of KI (4.0 g, 24.1mmol) in water (20 mL) was added dropwise at 0° C. and the reactionmixture was heated 50-60° C. for 2.5 h. The reaction mixture wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith 10% sodium thiosulfate (30 mL) followed by brine (30 mL) and thendried over MgSO₄. and solvent evaporated to give crude brown oil, whichwas purified by column chromatography over silica gel (Heptane-EtOAcgradient) to give 2.2 g, (57%) of2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester as a yellow oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ7.46 (d, J=8.8 Hz, 1H), 6.83 (d, J=6.3 Hz, 1H), 4.01-3.83 (m, 5H),1.96-1.86 (m, 1H), 1.69-1.58 (m, 1H), 1.51-1.39 (m, 1H), 1.28-1.18 (m,1H), 1.12-1.00 (m, 1H), 0.91 (d, J=6.3 Hz, 6H), 0.66-0.60 (m, 2H),0.55-047 (m, 2H), 0.42-0.34 (m, 2H), 0.26-0.18 (m, 2H); ¹³C NMR (75 MHz,CDCl₃/TMS): δ 173.2, 154.3 (d, ¹J_(CF)=243.4 Hz), 154.1, 127.1 (d,²J_(CF)=16.2 Hz), 125.5 (d, ²J_(CF)=26.4 Hz), 112.3 (d, ³J_(CF)=3.6 Hz),84.6 (d, ³J_(CF)=8.4 Hz), 74.5, 69.6, 41.9, 41.5, 26.0, 22.7, 22.2,10.2, 9.8, 3.3.

Step 7

2-(2-Cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester

To a solution of2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (0.2 g, 0.43 mmol) in anhydrous DME (10 mL)under argon was added 4-trifluoromethylphenylboronic acid (0.1 g, 0.53mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh₃)₄ (0.015 g, 0.013 mmol). Thereaction mixture was refluxed for 18 h, a water/EtOAc 15/15 mL mixturewas added and the organic phase was separated and dried over MgSO₄. Thesolvent was then evaporated to give a yellow oil which was purified bycolumn chromatography over silica gel (Heptane-EtOAc gradient) to give0.18 of2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester as a light yellow oil. ¹H NMR (300 MHz,CDCl₃/TMS): δ 7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1Hz, 1H), 4.09 (t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz,2H), 2.04-1.90 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05(m, 2H), 0.95 (d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H).¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 154.3 (d, ¹J_(CF)=239.7 Hz),151.9, 140.7, 132.0, 129.5, 126.6 (d, ²J_(CF)=16.9 Hz), 124.8 (q,³J_(CF)=3.7 Hz), 124.0 (q, ¹J_(CF)=271.6 Hz), 117.0 (d, ²J_(CF)=24.6Hz), 113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.

Step 8

2-(2-Cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid

2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.14 g, 0.29 mmol) was dissolved in amixture of EtOH/H₂O (9 ml/1 ml) and KOH 0.3 g added. The reactionmixture was refluxed for 2 h and after cooling the solvent wasevaporated. Water (10 mL) was added and the reaction mixture wasextracted with EtOAc (3×10 mL). The combined organic extracts were driedover MgSO₄ and evaporated under reduced pressure to an oil which waspurified by column chromatography over silica gel (Heptane-EtOAcgradient) to give 0.12 g of a white solid. A second chromatography ofthe solid gave 0.03 g (25%) of pure2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid product as a crystalline white solid. M.P.=110-111° C., ¹H NMR (300MHz, CDCl₃/TMS): δ 8.99 (br s 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz,1H), 6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz,2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05(m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9Hz, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.2, 154.7 (d, ¹J_(CF)=239.8Hz), 152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, ²J_(CF)=16.2 Hz),124.8 (q, ³J_(CF)=3.6 Hz), 124.0 (q, ¹J_(CF)=270 Hz), 117.2 (d,²J_(CF)=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.

Example 4852-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

Step 1

Ethyl 2-(3-bromo-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.11mol) in 200 ml of CCl₄, was slowly added bromine (18.8 g, 0.11 mol)dissolved in 10 ml of CCl₄ at 0° C. for 30 min. The reaction mass wasstirred for another 30 min at 0° C. After completion of the reaction,the mixture was poured onto crushed ice and extracted with DCM (×2). Thecombined organic layers were washed with water, and 10% sodiumbi-sulfite solution, dried over Na₂SO₄, filtered and concentrated invacuo to give ethyl 2-(3-bromo-4-hydroxyphenyl)acetate in 78% yield.(22.4 g). ¹HNMR (CDCl3): 7.42 (s, 1H); 7.14 (d, 1H); 6.97 (d, 1H); 5.53(bs, 1H); 4.13 (q, 2H); 3.52 (s, 2H); 1.16 (t, 3H).

Step 2

Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(3-bromo-4-hydroxyphenyl)acetate (20 g,0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol) and themixture was refluxed. Sulfuryl chloride (6.8 ml 0.846 mol) was slowlyadded under over a period of 10 min. The reaction mixture was refluxedfor a further 5 h. Upon completion of reaction, the mixture was pouredonto crushed ice and extracted with DCM (×2). The combined organic layerwere washed with 10% NaHCO₃ solution and water, dried over Na₂SO₄,filtered and evaporated under vacuum to give ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g).¹HNMR (CDCl3): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H);3.48 (s, 2H); 1.29 (t, 3H).

Step 3

Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (4 g, 0.011 mol) and K₂CO₃(2.8 g, 0.02 mol) in 100 ml of DMSO was slowly added cyclopropylmethylbromide (1.46 ml, 0.017 mol) at room temperature. Upon completionof the addition, the reaction mixture was heated at 60° C. for 4 h. Uponcompletion of the reaction, the mixture was poured onto water andextracted with EtOAc (×2). The combined organic layers were washed withwater, dried over Na₂SO₄, filtered and concentrated in vacuo to giveethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate in 72%yield. (93.4 g). ¹HNMR (CDCl3): 7.38 (bs, 1H); 7.28 (s, 1H); 4.16 (q,2H); 3.87 (d, 2H); 3.58 (s, 2H); 1.38 (m, 1H); 1.28 (t, 3H); 0.63 (m,2H); 0.38 (m, 2H).

Step 4

Ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate

A mixture of ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (4 g, 0.011mol), 4-Trifluoromethyl phenylboronic acid (2.6 g, 0.012 mol), PalladiumTetrakis (triphenylphosphine) (1.3 g, 0.001 mol), Cesium carbonate (13.1g, 0.04 mol) in DMF/water mixture (100 ml/5 ml) was stirred overnight at100° C. Upon completion of reaction, the precipitate were removed byfiltration. The filtrate was diluted with water and extracted with EtOActwice. The combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byFlash Column Chromatography to give ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetatein 57% yield. (2.7 g). ¹HNMR (CDCl3): 7.69 (bs, 4H); 7.36 (s, 1H); 7.17(s, 1H); 4.18 (q, 2H); 3.59 (s, 2H); 3.39 (d, 2H); 1.28 (t, 3H); 0.96(m, 1H); 0.41 (m, 2H); 0.01 (m, 2H).

Step 5

Ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

To a suspension of NaH (37 mg, 50% suspension, 0.79 mmol) in 25 ml ofDMF was slowly added a mixture of ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(300 mg, 0.719 mmol) and cyclopropylmethyl bromide (108 mg, 0.782 mmol)in 20 ml of DMF at 0° C. for 15 min under nitrogen atmosphere. Uponcompletion of the addition, the mixture was stirred for 15 min at 0° C.The reaction mixture was poured onto crushed ice and extracted withEtOAc (×2). The combined organic layers were washed with water andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by Flash column Chromatography to give ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoatein 62% yield. (0.210 g). ¹HNMR (CDCl3): 7.69 (s, 4H); 7.41 (s, 1H); 7.21(s, 1H); 4.19 (q, 2H); 3.63 (t, 1H); 3.41 (d, 2H); 1.94 (m, 1H); 1.78(m, 1H); 1.27 (t, 3H); 0.97 (bs, 1H); 0.72 (bs, 1H); 0.42 (m, 4H); 0.13(m, 2H); 0.1 (m, 2H).

Step 6

2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

A mixture of ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(100 mg, 0.214 mmol) and lithium hydroxide monohydrate (27 mg, 0.642mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirredfor 3 h at room temperature. Upon completion of reaction, the volatileswere removed under reduced pressure. The residue was diluted with water,acidified with 5% HCl solution and extracted with EtOAc (×2). Thecombined organic layers were washed with water, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by FlashColumn Chromatography to give2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid in 56% yield. (52.6 mg). ¹HNMR (CDCl3): 7.71 (s, 4H); 7.42 (s, 1H);7.23 (s, 1H); 3.68 (t, 1H); 3.41 (d, 2H); 1.93 (m, 1H); 1.77 (m, 1H);0.97 (bs, 1H); 0.71 (bs, 1H); 0.42 (m, 4H); 0.12 (m, 2H); 0.1 (m, 2H).

Example 4142-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution compound ethyl2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (6 g), in drymethanol (100 mL) was added Pd(OH)₂ under an atmosphere of nitrogen. Thereaction mixture was stirred for 5 h under an atmosphere of hydrogen.The reaction mixture was filtered through Celite™, washed with methanoland concentrated to dryness under reduced pressure. The crude materialwas purified by column chromatography to yield ethyl2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate (4 g, 72%). ¹HNMR(CDCl3, 200 MHz): 6.80 (s, 1H); 6.62 (s, 1H); 5.35 (bs, 1H); 4.13 (q,2H); 3.41 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97(d, 6H).

Step 2

Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate

Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate 1 (4 g,0.012 mol) was dissolved in a mixture of ACN/H₂O/HCl 60 mL/30 mL/8 mL at0° C. A solution of NaNO₂ (0.919 g, 1.1 eq) in water (10 mL) was addeddropwise at 0° C. and the reaction mixture was stirred for 1 h at 0° C.A solution of CuCl (5.99 g, 0.060 mol) in water (10 mL) was addeddropwise to the reaction mixture at 0° C. The reaction mixture was thenheated to 50° C. for 2.5 h. upon which the mixture was poured into icewater, extracted with ethyl acetate (3×100 mL) The combined organiclayers were washed with water (200 mL) and brine (100 mL), dried overNaSO₄ and concentrated in vacuo to give crude black oil which waspurified by chromatography over silica gel (hexane/EtOAc) to give ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow oil2.2 g, (47.3%). ¹HNMR (CDCl3, 200 MHz): 7.38 (s, 1H); 7.4 (s, 1H); 5.80(bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H);1.21 (t, 3H), 0.97 (d, 6H);

Step 3

Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate (2 g, 0.57 mmol)and K₂CO₃ (1.58 g, 0.011 mol) in dry DMF (20 mL), slowly addedtrifluoroethyl iodide (7.2 g, 3.39 ml, 0.034 mol) at room temperature.Upon completion of the addition, the reaction mixture was slowly heatedto 100° C. for 4 h. Upon completion, the reaction mixture was pouredinto water and extracted with ethyl acetate (2×50 mL). The combinedorganic layer were washed with water, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash columnchromatography over silica gel (hexane/EtOAc) to give ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(1.4 g, 60% yield). ¹HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H);4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H);1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 4

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

A mixture of ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(1 g, 1 eq), 4-Trifluoromethyl phenylboronic acid (2.6 g, 1.4 eq),Pd(PPh₃)₄ (1.3 g, 0.1 eq) and Cesium Fluoride (13.1 g, 2 eq) in DME (30ml) was stirred for overnight at 100° C. Upon completion, theprecipitate was removed by filtration. The filtrate was diluted withwater and extracted with ethyl acetate (2×50 mL). The combined organiclayers were washed with water followed by brine, dried over Na₂SO₄ andconcentrated under vacuo. The residue was purified by Flash ColumnChromatography to give ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoatein 74% yield (1.08 g). ¹HNMR (CDCl3, 400 MHz): 7.68 (m, 5H), 7.43 (s,1H); 7.24 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m,1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 5

2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

A mixture of ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(800 mg, mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) ina MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h atroom temperature. Upon completion of the reaction, the volatiles wereremoved under reduced pressure. The residue was diluted with water,acidified with 5% HCl solution and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by Flash Column Chromatography to give2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid in 88% yield (670 mg).

Or alternatively example 414 may be synthesized via the followingprocedures:

Step 1

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.75 g, 1.70 mmol) was dissolved in anhydrous DMF (20 mL), NaH (60% wt.in paraffin oil, 0.049 g, 2.04 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature, upon which isobutylbromide (0.2 mL, 1.87 mmol), was added in a drop wise manner at 0° C.The reaction mixture was stirred an additional 1 h at 0° C. and thensaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic layers werewashed with water (2×10 mL) and brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a colorlessoil, witch was purified by flash column chromatography to give ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(0.5 g, 59% yield) as a thick liquid.

Step 2

2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid

A mixture of ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(0.6 g, 1.21 mmol) and lithium hydroxide monohydrate (0.509 g, 12.1mmol) in MeOH/THF/Water a solvent mixture (10 mL/10 mL/10 mL) wasstirred for 4 h at room temperature. After completion of reactionvolatiles were removed under reduced pressure. The residue was dilutedwith water, acidified with 5% HCl solution and extracted with ethylacetate (3×20 mL). The combined organic layers washed with water, driedover Na₂SO₄, filtered and evaporated under reduced pressure. The residuewas purified by Flash Column Chromatography to give2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (0.4 g, 72% yield) as a white solid.

Example 10552-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoicAcid

Step 1

Diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate

To a solution of diethyl isobutylmalonate (50.0 g, 231 mmol) inanhydrous DMF (200 mL) cooled in an ice bath was added NaH (60%, 11.1 g,277 mmol) in small portions. After the addition, the reaction mixturewas stirred at 0° C. for 10 min and then at room temperature for 30 min.5-Chloro-2-nitrobenzotrifluoride (47.3 g, 210 mmol) in anhydrous DMF (50mL) was added dropwise and the mixture was stirred at room temperaturefor two days. The DMF was removed under high vacuum and the residue wasdiluted with ethyl acetate (400 mL). Water (400 mL) was added dropwise;ammonium chloride (25 g) was added and the layers were separated. Theorganic layer was washed with brine (400 mL), dried over sodium sulfate,and concentrated under reduced pressure to give a red-brown oil, whichwas purified by silica-gel flash chromatography eluting withheptane/ethyl acetate (12:1) to give the desired product diethyl2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 87%)as a yellow oil: ¹H NMR (300 MHz, CDCl₃): δ 8.07 (s, 1H), 7.94 (d, 2H,J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 4.25 (m, 4H), 2.33 (d, 2H, J=6.6 Hz),1.51 (m, 1H), 1.26 (t, 6H, J=7.2 Hz), 0.84 (d, 6H, J=6.6 Hz); ¹³C NMR(75 MHz, CDCl₃): δ 169.23, 146.71, 142.86, 132.94, 127.94 (q, J=5 Hz),124.55, 123.12 (q, J=33 Hz), 121.79 (q, J=272 Hz), 62.19, 61.59, 44.16,24.66, 23.66, 13.89.

Step 2

4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid

To a solution of diethyl2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 184mmol) in acetic acid (500 mL) were added water (157 mL) and concentratedH₂SO₄ (55 mL) carefully. The reaction mixture was refluxed for threedays and then concentrated under reduced pressure. The residue wasdiluted with water (400 mL) and extracted with ethyl acetate (6×100 mL).The combined organic extracts were washed with water (400 mL), driedover sodium sulfate, and concentrated under reduced pressure to give abrown oil. The residue was purified by silica-gel flash chromatographyeluting with heptane/EtOAc (5:1 and then 2:1) to give4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.5 g,76%) as a yellowish oil: ¹H NMR (300 MHz, CDCl₃): δ 11.51 (s, 1H, br),7.87 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.71 (d, 1H, J=8.4 Hz), 3.84 (t,1H, J=7.8 Hz), 2.06 (m, 1H), 1.72 (m, 1H), 1.49 (m, 1H), 0.95 (d, 3H,J=6.6. Hz), 0.94 (d, 3H, J=6.3 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 178.76,147.09, 143.94, 132.66, 127.70 (q, J=5 Hz), 125.40, 123.95 (q, J=34 Hz),121.74 (q, J=271 Hz), 42.16, 25.96, 22.44, 22.09.

Step 3

4-Methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester

To a solution of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoicacid (42.3 g, 139 mmol) in absolute ethanol (300 mL) was addedconcentrated sulfuric acid (95-98%, 9.0 mL) and the solution was heatedat reflux overnight. The reaction mixture was concentrated under reducedpressure; the residue was treated with a solution of sodium carbonate(5%, 300 mL) and the mixture was extracted with ethyl acetate (300 mL).The organic layer was washed with brine (300 mL), dried over sodiumsulfate, and concentrated under reduced pressure. Purification bysilica-gel flash chromatography eluting with heptane/EtOAc (10:1) gave4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester(38.4 g, 83%) as a yellowish oil: ¹HNMR (300 MHz, CDCl₃): δ 7.90 (d, 1H,J=8.4 Hz), 7.82 (s, 1H), 7.74 (dd, 1H, J=8.4, 1.5 Hz), 4.18 (m, 2H),3.83 (t, 1H, J=7.5 Hz), 2.06 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 1.27(t, 3H, J=7.2 Hz), 0.97 (d, 3H, J=6.6 Hz), 0.96 (d, 3H, J=6.3 Hz); ¹³CNMR (75 MHz, CDCl₃): δ 172.24, 146.83, 145.04, 132.40, 127.51 (q, J=5Hz), 125.28, 123.80 (q, J=32 Hz), 121.78 (q, J=272 Hz), 61.45, 49.45,42.65, 26.03, 22.41, 22.17, 14.10.

Step 4

2-(4-Amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester

A suspension of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoicacid ethyl ester (38.3 g, 115 mmol), tin (II) chloride (87.2 g, 460mmol) and water (16.6 g, 920 mmol) in ethanol (500 mL) was heated atreflux for four hours. The reaction mixture was concentrated underreduced pressure; the residue was treated with ethyl acetate (300 mL)and aqueous NaOH solution (1 N, 2.5 L). The aqueous layer was extractedwith ethyl acetate (3×600 mL). The combined organic layers were washedwith brine (1 L), dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by silica-gel flash chromatographyeluting with heptane/ethyl acetate (10:1) to give2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester(31.1 g, 89%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃): δ 7.35 (d, 1H,J=2.1 Hz), 7.27 (dd, 1H, J=8.4, 2.1 Hz), 6.69 (d, 1H, J=8.4 Hz), 4.10(m, 4H), 3.54 (t, 1H, J=7.8 Hz), 1.91 (m, 1H), 1.58 (m, 1H), 1.44 (m,1H), 1.21 (t, 3H, J=6.9 Hz), 0.90 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.6Hz); ¹³C NMR (75 MHz, CDCl₃): δ 174.14, 143.45, 132.22, 128.58, 125.91(q, J=4 Hz), 124.80 (q, J=271 Hz), 117.35, 113.60 (q, J=29 Hz), 60.60,48.54, 42.35, 25.77, 22.46, 22.18, 14.04.

Step 5

2-(4-Hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acidethyl ester

To sulfuric acid (95-98%, 20.0 mL) was added2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester(6.06 g, 20.0 mmol). The mixture was cooled to 0° C. and water (30.0 mL)was added dropwise. A solution of NaNO₂ (1.66 g, 24.0 mmol) in water (12mL) was added dropwise and the mixture was stirred for additional 20min. A few crystals of urea were added to decompose any excess NaNO₂. Asolution of cupric nitrate (466 g, 2.00 mol) in water (880 mL) wasadded, followed by addition of Cu₂O (2.86 g, 20.0 mmol). The mixture wasstirred for 5 min and diethyl ether (1 L) was added. The organic extractwas washed with brine (500 mL), dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by silica-gel flashchromatography eluting with heptane/ethyl acetate (20:1) to give2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acidethyl ester (2.20 g, 31%) as a yellow oil: HRMS (DIP-CI-MS): calcd forC₁₅H₁₉NO₅F₃ (M+H)⁺: 350.1215, found 350.1240; ¹H NMR (300 MHz, CDCl₃): δ11.13 (s, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 4.15 (m, 2H), 3.69 (t, 1H,J=7.8 Hz), 2.00 (m, 1H), 1.62 (m, 1H), 1.47 (m, 1H), 1.25 (t, 3H, J=7.2Hz), 0.94 (d, 3H, J=6.3 Hz), 0.93 (d, 3H, J=6.6 Hz); ¹³C NMR (75 MHz,CDCl₃): δ 172.75, 152.45, 134.67 (q, J=5 Hz), 134.29, 131.40, 127.90,122.35, (q, J=271 Hz), 121.42 (q, J=32 Hz), 61.51, 48.76, 42.76, 26.23,22.60, 22.42, 14.32.

Step 6

2-(4-Cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester

To a solution of2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acidethyl ester (2.66 g, 7.62 mmol), cyclopropanemethanol (0.60 g, 8.38mmol) and triphenylphosphine (2.40 g, 9.14 mmol) in anhydrous THF (32mL) was added diethyl azodicarboxylate (40 wt % solution in toluene,3.98 g, 9.14 mmol) dropwise. The reaction mixture was stirred at roomtemperature for two days and then concentrated under reduced pressure.The residue was triturated with THF/hexane (1:5, 3×15 mL). The combinedextracts were concentrated under reduced pressure to give a yellowsolid, which was purified by silica-gel flash chromatography elutingwith heptane/ethyl acetate (60:1 and then 10:1) to give2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester (1.89 g, 61%) as a colorless oil: ¹H NMR (300 MHz,CDCl₃): δ 7.92 (s, 1H), 7.73 (s, 1H), 4.06 (m, 2H), 3.79 (d, 2H, J=7.2Hz), 3.64 (t, 1H, J=7.5 Hz), 1.93 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H),1.24 (m, 1H), 1.17 (t, 3H, J=6.9 Hz), 0.86 (m, 6H), 0.56 (d, 2H, J=6.6Hz), 0.27 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 172.49, 149.98, 144.40,135.55, 130.96 (q, J=5 Hz), 128.29, 126.77, (q, J=31 Hz), 122.37 (q,J=272 Hz), 82.03, 61.37, 48.74, 42.66, 26.04, 22.36, 22.32, 14.14,10.66, 3.39.

Step 7

2-(3-Amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester

A mixture of2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester (1.85 g, 4.59 mmol) and Pd/C (1.85 g) in ethanol and 1N HCl (4.60 mL) was hydrogenated under 36 psi H₂ in a Parr apparatus.After 4 h, the reaction mixture was filtered through Celite 521®. Thefiltrate was concentrated under reduced pressure to give a yellow oil.The residue was treated with an aqueous solution of sodium carbonate (3g in 100 mL of water) and the resulting solution was extracted withethyl acetate (100 mL). The organic layer was dried over sodium sulfateand concentrated under reduced pressure to give a brown oil, which waspurified by silica-gel flash chromatography eluting with a gradient ofheptane/ethyl acetate (from 10:1 to 2:1) to give2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester (0.88 g, 51%) as a light pink oil: ¹HNMR (300 MHz,CDCl₃): δ 6.83 (s, 1H), 6.80 (s, 1H), 4.04 (m, 2H), 3.85 (s, 2H), 3.66(d, 2H, J=6.9 Hz), 3.45 (t, 1H, J=7.8 Hz), 1.84 (m, 1H), 1.49 (m, 1H),1.39 (m, 1H), 1.22 (m, 1H), 1.14 (t, 3H, J=7.2 Hz), 0.82 (m, 6H), 0.56(d, 2H, J=7.5 Hz), 0.27 (d, 2H, J=4.5 Hz); ¹³C NMR (75 MHz, CDCl₃): δ173.61, 142.71, 141.25, 135.51, 123.75 (q, J=30 Hz), 123.52 (q, J=271Hz), 118.46, 115.52 (q, J=5 Hz), 77.88, 60.70, 49.03, 42.53, 25.86,22.40, 22.31, 14.07, 10.98, 3.19.

Step 8

2-(4-Cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester

To a solution of p-toluenesulfonic acid monohydrate (0.308 g, 1.62 mmol)in acetonitrile (2.3 mL) was added2-(3-amino-4-cyclopropylmethoxy-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester (0.20 g, 0.54 mmol). The resulting suspension of theamine salt was cooled in an ice bath. A solution of sodium nitrite(0.0745 g, 1.08 mmol) in water (0.32 mL) was added dropwise, followed byaddition of a solution of KI (1.79 g, 10.8 mmol) in water (2.0 mL). Thereaction mixture was stirred in the ice bath for one hour and then atroom temperature for one hour. TLC showed that the reaction wascompleted. Water (20 mL) was added and then an aqueous solution ofsodium bicarbonate (1 M) to adjust the pH to 8. Ethyl acetate (20 mL)was added for extraction. The organic layer was washed with aqueousNa₂S₂O₄ solution (10%, 20 mL) and brine (20 mL), dried over Na₂SO₄, andconcentrated under reduced pressure to give a brown oil, which waspurified by silica-gel flash chromatography eluting with heptane/ethylacetate (30:1) to give2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester (0.15 g, 57%) as a yellowish oil: ¹HNMR (300 MHz,CDCl₃): δ 7.93 (s, 1H), 7.52 (s, 1H), 4.11 (m, 2H), 3.83 (d, 2H, J=7.2Hz), 3.59 (t, 1H, J=7.5 Hz), 1.95 (m, 1H), 1.50 (m, 3H), 1.22 (t, 3H,J=6.9 Hz), 0.91 (d, 3H, J=6.3 Hz), 0.90 (d, 3H, J=6.3 Hz), 0.64 (m, 2H),0.43 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 172.96, 155.55, 142.66, 136.98,126.94 (q, J=5 Hz), 124.87 (q, J=30 Hz), 122.64 (q, J=272 Hz), 93.73,79.79, 61.06, 48.53, 42.65, 26.01, 22.39, 14.16, 10.75, 3.36.

Step 9

2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoicacid ethyl ester

A mixture of2-(4-cyclopropylmethoxy-3-iodo-5-trifluoromethyl-phenyl)-4-methyl-pentanoicacid ethyl ester (0.14 g, 0.29 mmol), 4-(trifluoromethyl)benzeneboronicacid (0.089 g, 0.47 mmol), Pd(dppf)Cl₂ (0.023 g, 0.031 mmol) and asolution of aqueous sodium carbonate (2 M, 0.31 mL, 0.62 mmol) in1,4-dioxane (4 mL) was degassed and heated at 100° C. for ten days. Thereaction mixture was concentrated under reduced pressure; the residuewas treated with water (30 mL) and ethyl acetate (30 mL). The organiclayer was washed with brine (30 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with heptane/ethyl acetate (100:1) togive a colorless oil (0.11 g), which was further purified by flashchromatography on silica gel 100 C₁₈-reversed phase eluting withMeOH/H₂O (5:1 to 20:3) to give2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoicacid ethyl ester (0.05 g, 34%) as a white solid: ¹H NMR (300 MHz,CDCl₃/TMS): δ 7.73 (m, 4H), 7.58 (s, 1H), 7.48 (s, 1H), 4.13 (m, 2H),3.70 (t, 1H, J=7.5 Hz), 3.27 (d, 2H, J=7.2 Hz), 2.00 (m, 1H), 1.67 (m,2H), 1.51 (m, 1H), 1.25 (t, 3H, J=7.2 Hz), 0.93 (m, 8H), 0.45 (d, 2H,J=7.5 Hz); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.35, 153.80, 140.99,135.48, 135.40, 134.05, 130.05 (q, J=32 Hz), 129.88 (q, J=32 Hz),129.42, 126.41 (q, J=5 Hz), 125.33 (q, J=4 Hz), 124.06 (q, J=270 Hz),123.48 (q, J=270 Hz), 79.47, 60.98, 49.21, 42.87, 26.19, 22.46, 14.22,10.56, 3.13.

Step 10

2-(6-Cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoicacid

A mixture of2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoicacid ethyl ester (0.04 g, 0.08 mmol) and aqueous KOH (1.4 M, 0.4 mL) inethanol (5 mL) was stirred at room temperature for two days. After thesolvent was removed under reduced pressure, the residue was diluted withwater (30 mL), acidified with 1 N HCl to pH 1, and then extracted withethyl acetate (30 mL). The organic layer was dried over sodium sulfate,concentrated under reduced pressure and freeze-dried overnight to givethe desired carboxylic acid2-(6-cyclopropylmethoxy-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoicacid (0.04 g, 100%) as a white solid: mp 148-149° C.; HRMS (ESI-TOF):calcd for C₂₄H₂₃O₃F₆Na₂ (M−H+2Na)⁺: 519.1341, found 519.1366; ¹H NMR(300 MHz, CDCl₃/TMS): δ 7.72 (m, 4H), 7.59 (s, 1H), 7.48 (s, 1H), 3.73(m, 1H), 3.27 (d, 2H, J=6.9 Hz), 2.02 (m, 1H), 1.69 (m, 1H), 1.56 (m,1H), 1.28 (m, 1H), 0.94 (m, 8H), 0.46 (m, 2H); the proton of COOH wasnot observed; ¹³C NMR (75 MHz, CDCl₃/TMS): δ 178.95, 154.12, 140.82,135.61, 134.49, 134.24, 130.18 (q, J=32 Hz), 129.44 (q, J=32 Hz),129.40, 126.50 (q, J=5 Hz), 125.39 (q, J=4 Hz), 124.04 (q, J=270 Hz),123.40 (q, J=271 Hz), 79.55, 48.91, 42.35, 26.07, 22.49, 22.35, 10.58,3.15; HPLC purity: 95.2%, retention time=11.78 min.

Example 7542-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoicacid

Step 1.

Cyclopropylmethyl2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate

To a solution of2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (0.2 g, 0.43 mmol) in DME (anhydrous, 10 mL)under argon atmosphere was added 4-trifluoromethylphenylboronic acid(0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh₃)₄ (0.015 g,0.013 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100°C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layerswere separated. The organic phase was dried over MgSO₄ and evaporated togive a crude yellow oil, which was purified by silica gel gradientcolumn chromatograph using Heptane-EtOAc (60:1-9:1) to givecyclopropylmethyl2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoateas a yellowish oil (0.18 g, 90%). ¹H NMR (300 MHz, CDCl₃/TMS): δ7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09(t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90(m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95(d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). ¹³C NMR (75MHz, CDCl₃/TMS): δ 173.5, 154.3 (d, ¹J_(CF)=239.7 Hz), 151.9, 140.7,132.0, 129.5, 126.6 (d, ²J_(CF)=16.9 Hz), 124.8 (q, ³J_(CF)=3.7 Hz),124.0 (q, ¹J_(CF)=271.6 Hz), 117.0 (d, ²J_(CF)=24.6 Hz), 113.6, 74.1,69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.

Step 2

2-(4-benzo[1,2,5]oxadiazol-5-yl-5-cyclopropylmethoxy-2-fluoro-phenyl)-4-methylpentanoicacid

Cyclopropylmethyl2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate(0.14 g, 0.29 mmol) was dissolved in a mixture of EtOH/H₂O (9 mL/1 mL)and KOH (0.3 g) was added. The reaction mixture was refluxed for 2 h andafter cooling the solvent was evaporated. Then, 6 N HCl was added toadjust the pH to 5, and the reaction mixture was extracted with EtOAc(3×10 mL). The combined organic phases were dried over MgSO₄ andevaporated under reduced pressure to give a colorless oil. Purificationby gradient column chromatography on silica gel Heptane-EtOAc (50:1-9:1)gave2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoicacid as a white solid (0.12 g, quantitative); pure portion (0.03 g,25%); white microcrystals, M.P.=110-111° C., ¹H NMR (300 MHz,CDCl₃/TMS): δ 8.99 (br s, 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H),6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz, 2H),2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05 (m,2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9 Hz,2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.2, 154.7 (d, ¹J_(CF)=239.8 Hz),152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, ²J_(CF)=16.2 Hz), 124.8 (q,³J_(CF)=3.6 Hz), 124.0 (q, ¹J_(CF)=270 Hz), 117.2 (d, ²J_(CF)=25.2 Hz),113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.

Example 29592-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid

Step 1

2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester

To a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol)in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g,0.57 mol) over 20 min. at 0° C. The reaction mixture was stirred at 0°C. for 0.5 h, then warmed to 25° C. The reaction mixture was cooled downto 0° C. again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31mol) in DMF (150 mL) was added dropwise at 0° C. The reaction mixturewas stirred at 25° C. for 16 h. After cooling, the reaction mixture waspoured into ice water (200 mL) and extracted with EtOAc (3×100 mL). Thecombined organic phases washed with water (3×100 mL), brine (100 mL),and dried (MgSO₄). Evaporation of the solvent under reduced pressuregave a brown oil. The crude product (92.0 g, 82%) was used for the nextstep without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.03 (t, J=8.4Hz, 1H), 7.70 (dd, J=12.9, 1.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H),4.25-4.18 (m, 4H), 2.28 (d, J=6.3 Hz, 2H), 1.54-1.45 (m, 1H), 1.25 (t,J=7.0 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ169.2, 154.5 (d, ¹J_(CF)=263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1(d, ³J_(CF)=3.6 Hz), 118.6 (d, ²J_(CF)=23.3 Hz), 62.0, 60.3, 44.1, 24.7,23.6, 13.9.

Step 2

2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid

2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester (92.0g, 0.26 mol) was dissolved in AcOH/H₂O/H₂SO₄ (96%) (500 mL/200 mL/70 mL)and the reaction mixture was refluxed for 24 h. After cooling andevaporation, water (300 mL) was added. The reaction mixture wasextracted with EtOAc (3×100 mL). The combined organic phases were washedwith water (3×100 mL), brine (100 mL) and dried (MgSO₄). The evaporationof solvent under reduced pressure gave a brown oil (61 g, quantitative),which was used for the next step without purification. ¹H NMR (300 MHz,CDCl₃/TMS): δ 8.07-8.01 (m, 1H), 7.33-7.26 (m, 2H), 3.79-3.73 (m, 1H),2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m,6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 178.3, 156.0 (d, ¹J_(CF)=232.5 Hz),147.0, 136.0, 126.2, 124.3, 118.1 (d, ²J_(CF)=30 Hz), 49.3, 42.0, 25.8,22.4, 22.0.

Step 3

2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester

2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.12 mmol)was dissolved in EtOH (100 mL) and H₂SO₄ (96%, 5 mL) was added. Thereaction mixture was refluxed for 3 h and the solvent evaporated. Water(100 mL) was added and the reaction mixture was extracted with EtOAc(3×100 mL). The combined organic phases were washed with saturatedNaHCO₃ solution (50 mL), water (100 mL) and brine (100 mL), and thendried over MgSO₄. Evaporation of the solvent under reduced pressure gavea brown oil (31.0 g, 97%), which was used for the next step withoutpurification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.03 (t, J=8.4 Hz, 1H),7.33-7.26 (m, 2H), 4.17-4.11 (m, 2H), 3.73 (t, J=7.6 Hz, 1H), 2.10-1.94(m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.0 Hz, 3H),0.95-0.92 (m, 6H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ 172.2, 155.3 (d,¹J_(CF)=265.0 Hz), 148.3 (d, ³J_(CF)=8.4 Hz), 136.5, 126.1, 124.1 (d,³J_(CF)=3.6 Hz), 117.8 (d, ²J_(CF)=21.6 Hz), 61.3, 49.4, 42.3, 25.9,22.5, 22.1, 14.1.

Step 4

2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester

Cyclopropylmethanol (80.0 g, 1.11 mol) was treated with n-BuLi (2.5 M inhexane, 9.1 g, 57 mL, 0.14 mol) at a temperature ranging from −15 to 0°C. The reaction mixture was stirred for 1 h at 25° C. Then, a solutionof 2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester incyclopropylmethanol (30 mL) was added at 25° C. and the reaction mixturewas stirred for 16 h. Water (100 mL) was added and the reaction mixturewas extracted with EtOAc (3×100 mL). The combined organic phases werewashed with water (3×100 mL), brine (100 mL), and dried (MgSO₄).Evaporation of the solvent under reduced pressure gave a brown oil,which was purified by silica gel gradient column chromatography by useof Heptane-EtOAc (9:1-4:1) to give2-(3-cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester as a yellow oil (34.0 g, 93%). ¹H NMR (300 MHz,CDCl₃/TMS): δ 7.78 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.4 Hz,1H), 4.00-3.83 (m, 4H), 3.69 (t, J=8.0 Hz, 1H), 2.07-1.92 (m, 1H),1.69-1.60 (m, 1H), 1.52-1.42 (m, 1H), 1.32-1.20 (m, 1H), 1.19-1.00 (m,1H), 0.92 (d, J=6.3 Hz, 6H), 0.68-0.62 (m, 2H), 0.56-0.48 (m, 2H),0.42-0.38 (m, 2H), 0.26-0.21 (m, 2H); ¹³C NMR (75 MHz, CDCl₃/TMS): δ172.9, 152.3, 146.2, 138.8, 125.6, 119.8, 114.4, 74.2, 69.8, 49.8, 42.6,26.0, 22.5, 22.2, 10.0, 9.7, 3.3.

Step 5

2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester

2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (34.0 g, 94.2 mmol) was dissolved in AcOH (300mL) and water (20 mL). Then, Zn powder (60.0 g, 923 mmol) was added inportions. The reaction mixture was refluxed for 1 h and after coolingthe precipitate was filtered. The solvent was evaporated and water (150mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL)and the combined organic phases were washed with water (3×100 mL) andbrine (100 mL). Drying of the organic phase was performed with magnesiumsulfate. The evaporation of the solvent gave crude product as a brownoil, which was purified by silica gel gradient column chromatography byuse of Heptane-EtOAc to give2-(4-amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester as a yellow oil (23 g, 75%). ¹H NMR (300 MHz,CDCl₃/TMS): δ 6.73-6.61 (m, 3H), 3.94-3.78 (m, 6H), 3.53 (t, J=7.7 Hz,1H), 1.94-1.85 (m, 1H), 1.65-1.56 (m, 1H), 1.52-1.43 (m, 1H), 1.28-1.18(m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.64-0.58 (m, 2H),0.53-0.47 (m, 2H), 0.36-0.33 (m, 2H), 0.24-0.21 (m, 2H); ¹³C NMR (75MHz, CDCl₃/TMS): δ 174.6, 146.4, 135.3, 129.3, 120.5, 114.6, 111.2,73.1, 69.0, 49.2, 42.7, 25.8, 22.6, 22.4, 10.4, 9.8, 3.2.

Step 6

2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester

2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (16.3 g, 49.1 mmol) was dissolved in chloroform(200 mL) and N-chlorosuccinimide (5.3 g, 0.75 equiv, 39.6 mmol) wasadded. The reaction mixture was refluxed for 1 h and after coolingtreated with 10% potassium carbonate solution (100 mL). The reactionmixture was extracted with EtOAc (3×50 mL) and the combined organicphases were dried over magnesium sulfate. Evaporation of the solventgave the crude product as a brown oil, which was purified by silica gelgradient column chromatography by use of Heptane-EtOAc to give2-(4-amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester as a yellow oil (5 g, 36%). ¹H NMR (300 MHz,CDCl₃/TMS): δ 6.85 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.49 (t,J=7.7 Hz, 1H), 1.94-1.82 (m, 1H), 1.63-1.52 (m, 1H), 1.50-1.40 (m, 1H),1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.66-0.58(m, 2H), 0.53-0.47 (m, 2H), 0.37-0.32 (m, 2H), 0.25-0.20 (m, 2H); ¹³CNMR (75 MHz, CDCl₃/TMS): δ 174.2, 146.8, 132.6, 128.7, 120.6, 118.3,109.4, 73.6, 69.3, 49.0, 42.6, 25.9, 22.6, 22.4, 10.4, 9.8, 3.3.

Step 7

2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester

2-(4-Amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (5.0 g, 13.7 mmol) was dissolved in a mixture ofEtOH/H₂O/H₂SO₄ (96%) (65 mL/100 mL/2.5 mL) and the reaction mixture wascooled down to 0° C. A solution of NaNO₂ (0.95 g, 13.7 mmol) in water (5mL) was added dropwise at 0° C. and the reaction mixture was stirred for30 min. A solution of KI (7.0 g, 42.2 mmol) in water (20 mL) was addeddropwise at 0° C. The reaction mixture was heated to 50-60° C. for 2.5h. The reaction mixture was extracted with EtOAc (3×50 mL). The organiclayers were combined and washed with 10% sodium thiosulfate solution (30mL) followed by brine (30 mL). The organic phase was dried over MgSO₄and the solvent evaporated to give a crude brown oil, which was purifiedby silica gel gradient column chromatography by use of Heptane-EtOAc(20:1-9:1) to give2-(3-Chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester as a yellow oil (4.0 g, 62%). ¹H NMR (300 MHz,CDCl₃/TMS): δ 7.07 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.58 (t,J=7.7 Hz, 1H), 1.96-1.89 (m, 1H), 1.66-1.52 (m, 1H), 1.50-1.40 (m, 1H),1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.91 (d, J=6.6 Hz, 6H), 0.67-0.61(m, 2H), 0.56-0.50 (m, 2H), 0.45-0.40 (m, 2H), 0.26-0.21 (m, 2H); ¹³CNMR (75 MHz, CDCl₃/TMS): δ 173.2, 159.2, 141.6, 139.4, 121.4, 109.8,90.4, 74.0, 69.7, 49.4, 42.5, 26.0, 22.6, 22.3, 10.2, 9.8, 3.3.

Step 8

2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid cyclopropylmethyl ester

To a solution of2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (0.27 g, 0.57 mmol) in DME (anhydrous, 10 mL)under argon atmosphere were added5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]oxadiazole(0.15 g, 0.61 mmol), CsF (0.2 g, 1.32 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.021 g,0.029 mmol, need 0.06 mmol to complete the reaction!). The reactionmixture was refluxed for 18 h (oil bath, 100° C.). A mixture water/EtOAc(15 mL/15 mL) was added and the layers were separated. The organic phasewas dried over MgSO₄, then evaporated to give a crude yellow oil, whichwas purified by silica gel gradient column chromatography usingHeptane-EtOAc (20:1-9:1) to give2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.11 g, 41%) of as a yellowish oil. ¹H NMR(300 MHz, CDCl₃/TMS): δ 7.83 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33(m, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7Hz, 1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H),1.20-1.05 (m, 2H), 0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (brs, 2H), 0.19 (br s, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.4, 157.0,149.2, 148.3, 142.0, 138.7, 135.4, 133.5, 126.4, 121.6, 117.4, 114.9,110.6, 73.4, 69.8, 49.8, 42.8, 26.1, 22.5, 22.4, 10.0, 9.8, 3.3, 3.1

Step 9

2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid

2-(4-Benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.11 g, 0.23 mmol) was dissolved in amixture of EtOH/H₂O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added.The reaction mixture was refluxed for 2 h and after cooling the solventwas evaporated. Then, 6 N HCl was added to adjust the pH to 5, and thereaction mixture was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried over MgSO₄ and evaporated under reducedpressure to give2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid as a yellow oil (0.068 g, 70%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.40(br s, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J=9.3 Hz,1H), 6.97 (s, 1H), 6.73 (s, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.52 (t, J=7.7Hz, 1H), 1.90-1.81 (m, 1H), 1.62-1.53 (m, 1H), 1.50-1.39 (m, 1H),0.98-0.68 (m, 1H), 0.81 (d, J=6.1 Hz, 6H), 0.37-0.31 (m, 2H), 0.15-0.10(m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.1, 157.1, 149.1, 148.3,141.0, 138.6, 135.3, 133.7, 126.8, 121.6, 117.4, 115.0, 110.9, 73.4,49.4, 41.9, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 29952-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid

Step 1

2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid cyclopropylmethyl ester

To a solution of2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (0.18 g, 0.38 mmol) in DME (anhydrous, 10 mL)under argon atmosphere were added5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]thiodiazole(0.15 g, 0.57 mmol), CsF (0.14 g, 0.92 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.02 g,0.027 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100°C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layerswere separated. The combined organic phases were dried over MgSO₄ andevaporated to give a crude yellow oil, which was purified by silica gelgradient column chromatography by use of Heptane-EtOAc (20:1-9:1) togive2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.08 g, 50%) as a yellow oil. ¹H NMR (300MHz, CDCl₃/TMS): δ 7.83 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m,1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz,1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05(m, 2H), 0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H),0.19 (br s, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 157.1, 154.7,154.0, 141.4, 136.8, 133.7, 132.9, 126.9, 122.8, 121.6, 120.0, 110.8,73.3, 69.7, 49.7, 42.7, 26.1, 22.5, 22.5, 10.0, 9.8, 3.3, 3.1.

Step 2

2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid

2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.08 g, 0.19 mmol) was dissolved in amixture of EtOH and H₂O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) wasadded. The reaction mixture was refluxed for 2 h and after cooling thesolvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5,and the reaction mixture was extracted with EtOAc (3×10 mL). Thecombined organic phases were dried over MgSO₄ and evaporated underreduced pressure to give2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoicacid as a yellow oil (0.038 g, 55%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 8.02(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.13 (s, 1H),6.89 (s, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.68 (t, J=7.6 Hz, 1H), 2.04-1.96(m, 1H), 1.78-1.69 (m, 1H), 1.63-1.55 (m, 1H), 1.10-1.00 (m, 1H), 0.97(d, J=6.4 Hz, 6H), 0.50-0.39 (m, 2H), 0.22-0.12 (m, 2H). ¹³C NMR (75MHz, CDCl₃/TMS): δ 179.1, 157.2, 154.6, 154.0, 140.5, 136.7, 134.0,132.9, 127.8, 122.9, 121.6, 120.1, 111.0, 73.4, 49.4, 42.0, 25.9, 22.6,22.3, 10.0, 3.1.

Example 19042-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid

Step 1

2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester

To a solution of2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (0.09 g, 0.19 mmol) in DME (anhydrous, 10 mL)under argon atmosphere were added 4-trifluoromethylphenylboronic acid(0.04 g, 0.2 mmol), CsF (0.07 g, 0.46 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.06 g,0.08 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100°C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layerswere separated. The organic phase was dried over MgSO₄, then evaporatedto give a crude yellow oil, which was purified by silica gel gradientcolumn chromatography by use of Heptane-EtOAc (20:1-9:1) to give2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.063 g, 70%) as a yellowish oil. ¹H NMR(300 MHz, CDCl₃/TMS): δ 7.66 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H),7.08 (s, 1H), 6.88 (s, 1H), 4.01-3.86 (m, 2H), 3.77 (d, J=6.6 Hz, 2H),3.65 (t, J=7.9 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.62 (m, 1H), 1.59-1.48(m, 1H), 1.20-1.02 (m, 2H), 0.96-0.94 (m, 6H), 0.56-0.46 (m, 4H),0.27-0.25 (m, 2H), 0.16-0.15 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ173.5, 157.0, 141.2, 138.9, 133.6, 130.8 (two signals), 127.8, 124.5(q), 124.3 (q, ¹J_(CF)=271.0 Hz), 121.6, 111.0, 73.3, 69.7, 49.6, 42.7,26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.

Step 2

2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid

2-(2-Chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.06 g, 0.12 mmol) was dissolved in amixture of EtOH and H₂O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) wasadded. The reaction mixture was refluxed for 2 h and after cooling thesolvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5and the reaction mixture was extracted with EtOAc (3×10 mL). Thecombined organic phases were dried over MgSO₄ and evaporated underreduced pressure to give2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoicacid as a yellowish solid (0.046 g, 85%). M.p.=115-116° C. ¹H NMR (300MHz, CDCl₃/TMS): δ 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.08(s, 1H), 6.85 (s, 1H), 3.77 (d, J=6.4 Hz, 2H), 3.65 (t, J=7.7 Hz, 1H),2.04-1.94 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.52 (m, 1H), 1.15-0.89 (m,1H), 0.95 (d, J=6.4 Hz, 6H), 0.54-0.40 (m, 2H), 0.20-0.10 (m, 2H). ¹³CNMR (75 MHz, CDCl₃/TMS): δ 179.0, 157.1, 140.3, 138.8, 133.8, 130.8,129.3 (q), 128.2, 124.6, 124.3 (q, ¹J_(CF)=271.0 Hz), 121.6, 111.2,73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.

Example 32002-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoicacid

Step 1

2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester

To a solution of2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (0.32 g, 0.67 mmol) in DME (anhydrous, 20 mL)under argon atmosphere were added 4-chlorophenylboronic acid (0.13 g,0.83 mmol), CsF (0.24 g, 1.58 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.05 g,0.07 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100°C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layerswere separated. The organic phase was dried over MgSO₄ and evaporated togive a crude yellow oil, which was purified by silica gel gradientcolumn chromatography by use of Heptane-EtOAc (20:1-9:1) to give2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.26 g, 87%) as a yellowish oil. ¹H NMR(300 MHz, CDCl₃/TMS): δ 7.37 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H),7.07 (s, 1H), 6.86 (s, 1H), 3.96-3.89 (m, 2H), 3.76 (d, J=6.3 Hz, 2H),3.63 (t, J=7.7 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.48 (m, 2H), 1.21-1.00(m, 2H), 0.94 (d, J=6.3 Hz, 6H), 0.55-0.48 (m, 4H), 0.27-0.15 (m, 4H).¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.5, 157.1, 140.8, 133.7, 133.5, 133.0,131.8, 128.1, 127.8, 121.5, 111.1, 73.2, 69.6, 49.6, 42.6, 26.1, 22.6,22.5, 10.0, 9.8, 3.3, 3.0.

Step 2

2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoicacid

2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoicacid cyclopropylmethyl ester (0.18 g, 0.36 mmol) was dissolved in amixture of EtOH and H₂O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added.The reaction mixture was refluxed for 2 h and after cooling the solventwas evaporated. Then, 6 N HCl was added to adjust the pH to 5 and thereaction mixture was extracted with EtOAc (3×10 mL). The organic phasewas dried over MgSO₄ and evaporated under reduced pressure to give2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoicacid as a yellowish solid (0.15 g, 93%). M.p.=52-53° C. ¹H NMR (300 MHz,CDCl₃/TMS): δ 10.60 (br s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 3.63 (t,J=7.3 Hz, 1H), 1.99-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H),1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.40 (m, 2H), 0.22-0.12(m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.7, 157.2, 139.7, 134.0,133.4, 133.1, 131.8, 128.5, 127.9, 121.6, 111.3, 73.3, 49.4, 42.0, 25.9,22.6, 22.3, 10.0, 3.0.

Example 32014-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoicacid

Step 1

4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoicacid cyclopropylmethyl ester

To a solution of2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acidcyclopropylmethyl ester (0.53 g, 1.11 mmol) in DME (anhydrous, 20 mL)under argon atmosphere were added 4-chlorophenylboronic acid (0.25 g,1.30 mmol), CsF (0.41 g, 2.70 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.24 g,0.33 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100°C.). A mixture water and EtOAc (15 mL/15 mL) was added and the layerswere separated. The organic phase was dried over MgSO₄ and evaporated togive a crude yellow oil, which was purified by silica gel gradientcolumn chromatography by use of Heptane-EtOAc (20:1-9:1) to give4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoicacid cyclopropylmethyl ester (0.37 g, 70%) as a yellowish oil. ¹H NMR(300 MHz, CDCl₃/TMS): δ 7.48-7.42 (m, 2H), 7.17-7.14 (m, 2H), 7.07 (s,1H), 6.86 (s, 1H), 4.07-3.87 (m, 2H), 3.78 (d, J=6.3 Hz, 2H), 3.64 (t,J=7.7 Hz, 1H), 2.03-1.93 (m, 1H), 1.70-1.49 (m, 2H), 1.21-1.00 (m, 2H),0.95-0.93 (m, 6H), 0.56-0.49 (m, 4H), 0.27-0.19 (m, 4H). ¹³C NMR (75MHz, CDCl₃/TMS): δ 173.4, 156.9, 141.3, 134.9, 133.6, 132.5, 131.6,131.2, 129.9, 129.5, 126.6, 121.5, 110.8, 73.2, 69.6, 49.6, 42.6, 26.1,22.6, 22.4, 10.0, 9.8, 3.3, 3.1.

Step 2

4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoicacid

4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoicacid cyclopropylmethyl ester (0.37 g, 0.75 mmol) was dissolved in amixture of EtOH and H₂O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added.The reaction mixture was refluxed for 2 h and after cooling the solventwas evaporated. Then, 6 N HCl was added to adjust the pH to 5, and thereaction mixture was extracted with EtOAc (3×10 mL). The organic phasewas dried over MgSO₄ and evaporated under reduced pressure to give4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoicacid as a white solid (0.30 g, 90%). M.p.=118-119° C. ¹H NMR (300 MHz,CDCl₃/TMS): δ 9.70 (br s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.6Hz, 1H), 7.53 (dd, J=8.2, 1.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.78(d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 2.02-1.93 (m, 1H), 1.74-1.65(m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H),0.54-0.47 (m, 2H), 0.24-0.16 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ179.4, 157.0, 140.3, 134.8, 133.9, 132.5, 131.6, 131.3, 129.9, 129.6,127.0, 121.5, 111.1, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.

Example 19762-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoicacid

Step 1

5-Fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene

To a solution of 2,2,2-trifluoroethanol (28.2 g, 282.0 mmol) in toluene(120 mL) n-BuLi (1.6 M in hexane, 8.0 g, 80 mL, 125.0 mmol) was added at0° C. and the reaction mixture warmed up to 25° C. A solution of1,3,5-trifluoronitrobenzene (10.0 g, 56.5 mmol) in toluene (50 mL) wasadded dropwise. The reaction mixture was refluxed for 30 h and thenpoured into water (100 mL). The reaction mixture was extracted withEtOAc (3×100 mL). The organic layers were combined and dried over MgSO₄.The solvent was evaporated under reduced pressure to give5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene as a brown oil(18.0 g, 95%). The product was used for the next step withoutpurification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.47 (d, J=9.4 Hz, 2H),4.40 (q, J=8.0 Hz, 4H).

Step 2

2-[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethylester

To a solution of diethyl malonate (18.0 g, 114.9 mmol) in DMF (50 mL)was added sodium hydride (60% in mineral oil, 3.0 g, 125.0 mmol) at 0°C. The reaction mixture was stirred at 25° C. for 0.5 h and a solutionof 5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene (18.0 g,53.4 mmol) in DMF (30 mL) was added dropwise. The reaction mixture washeated 100° C. for 24 h. After cooling the reaction mixture was pouredinto water (300 mL) and extracted with EtOAc (3×50 mL). The combinedorganic phases were washed with water (3×100 mL), brine (100 mL) anddried (MgSO₄). Evaporation of the solvent under reduced pressure gave2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethylester as a brown oil (20.8 g, 80%). The crude product was used for thenext step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.91 (s,2H), 4.62 (s, 1H), 4.48 (q, J=8.0 Hz, 4H), 4.28-4.16 (m, 4H), 1.31-1.25(m, 6H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 166.4, 149.2, 136.7, 132.3,122.3 (q, ¹J_(CF)=276.6 Hz), 109.5 (two signals), 67.0 (q, ²J_(CF)=36.7Hz), 61.4, 41.6, 14.0.

Step 3

[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

Crude 2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic aciddiethyl ester (20.8 g, 43.6 mmol) was dissolved in a mixture of AcOH/12N HCl (150 mL/150 mL) and the reaction mixture was refluxed for 16 h.The solvent was evaporated and water (100 mL) was added. The reactionmixture was extracted with EtOAc (3×100 mL). The organic layers werecombined, washed with water (3×100 mL), and dried over MgSO₄. Thesolvent was evaporated under reduced pressure to give a brown solid,which was washed with a mixture of Heptane/Et₂O (100 mL/100 mL) to give[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethylester as a solid (10.0 g, 57%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.71 (s,2H), 4.45 (q, J=7.7 Hz, 4H), 4.18 (q, J=7.2 Hz, 2H), 3.63 (s, 2H), 1.28(t, J=7.1 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 169.7, 149.6, 138.5,132.4, 122.4 (q, ¹J_(CF)=277.6 Hz), 109.4 (two signals), 67.0 (q,²J_(CF)=37.2 Hz), 61.6, 41.4, 14.2.

Step 4

[4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethylester (10.0 g, 24.7 mmol) was dissolved in EtOH (200 mL) andhydrogenated at 50 psi, 25° C. for 16 h in the presence of Pd—C catalyst(10%, 1 g). The catalyst was filtered off and the solvent evaporated togive a crude brown oil, which was purified by silica gel gradient columnchromatography by use of Heptane-EtOAc to give[4-amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethylester as a yellow oil (8.3 g, 90%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.52(s, 2H), 4.37 (q, J=8.0 Hz, 4H), 4.14 (q, J=7.2 Hz, 2H), 3.90 (br s,2H), 3.48 (s, 2H), 1.25 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃/TMS):δ 171.4, 145.0, 126.3, 123.2, (q, ¹J_(CF)=277.6 Hz), 122.6, 110.0, 109.8(two signals), 66.8 (q, ²J_(CF)=35.5 Hz), 61.0, 41.0, 14.2.

Step 5

[4-Iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid ethyl ester

[4-Amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethylester (7.1 g, 18.9 mmol) was dissolved in MeCN (50 mL) and p-TsOH×H₂O(11.0 g, 57.9 mmol) was added. The reaction mixture was cooled down to−15° C. and NaNO₂ (1.6 g, 23.2 mmol) in water (1 mL) was added. Thereaction mixture was stirred at −15° C. for 0.5 h; then a solution of KI(15.0 g, 93.8 mmol) in water (10 mL) was added. The reaction mixture wasstirred at −15° C. for additional 0.5 h and quenched with 1 N NaHCO₃solution to pH 9-10. After addition of 10% NaHSO₃ solution (20 mL), thereaction mixture was extracted with EtOAc (3×50 mL). The combinedorganic phases were washed with saturated NaCl solution, dried (MgSO₄)and evaporated to give crude a brown oil (9.0 g), which was purified bygradient column chromatography on silica gel eluting with Heptane-EtOAc(9:1-3:1) to give[4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl esteras a white solid (3.8 g, 41%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 6.53 (s,2H), 4.40 (q, J=8.0 Hz, 4H), 4.16 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 1.26(t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 170.3, 157.7, 136.7,122.8 (q, ¹J_(CF)=277.6 Hz), 108.9 (two signals), 78.3, 67.0 (q,²J_(CF)=36.0 Hz), 61.3, 41.2, 14.2.

Step 6

[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-aceticacid ethyl ester

To a solution of [4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-aceticacid ethyl ester (0.8 g, 1.65 mmol) in DME (anhydrous, 15 mL) underargon atmosphere were added 4-trifluoromethylphenylboronic acid (0.4 g,2.10 mmol), CsF (0.6 g, 3.95 mmol), and Pd(PPh₃)₄ (0.3 g, 0.26 mmol).The reaction mixture was refluxed for 18 h (oil bath, 100° C.). Amixture of water and EtOAc (15 mL/15 mL) was added and the layers wereseparated. The organic phase was dried over MgSO₄ and evaporated to givea crude yellow oil, which was purified by silica gel gradient columnchromatography by use of Heptane-EtOAc (20:1-9:1) to give[2,6-bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-aceticacid ethyl ester (0.54 g, 70%) as a yellowish oil. ¹H NMR (300 MHz,CDCl₃/TMS): δ 7.64 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 6.68 (s,2H), 4.28-4.16 (6H), 3.63 (s, 2H), 1.29 (t, J=7.2 Hz, 3H). ¹³C NMR (75MHz, CDCl₃/TMS): δ 170.6, 155.3, 136.1, 135.5, 131.0, 129.4, 129.0,124.4 (q, ³J_(CF)=3.9 Hz), 124.2, 122.9, 119.0, 109.2 (two signals),66.5 (q, ²J_(CF)=35.5 Hz), 61.3, 41.5, 14.2.

Step 7

2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoicacid

[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-aceticacid ethyl ester (0.52 g, 1.03 mmol) was dissolved in anhydrous DMF (5mL) and sodium hydride (60% in oil, 0.05 g, 2.08 mmol) was added at 0°C. The reaction mixture was stirred at 0° C. for 20 min and isobutylbromide (0.15 g, 1.09 mmol) was added. The reaction mixture was stirredfor 1 h at the same temperature and at 25° C. for 15 min., followed byaddition of saturated ammonium chloride solution (10 mL). The reactionmixture was extracted with ethyl acetate (2×20 mL) and the combinedorganic phases were washed with water (3×20 mL), saturated sodiumchloride solution (10 mL) and dried over magnesium sulfate. Evaporationgave the crude yellow oil (0.56 g), which was purified by silica gelcolumn chromatography with Heptane/EtOAc to give a white solid (0.24 g).The resulting solid was dissolved in EtOH (10 mL), and H₂O (1 mL) andpotassium hydroxide (0.2 g) were added. The reaction mixture wasrefluxed for 2 h and solvent evaporated. Then, 6 N HCl was added toadjust the pH to 3-5 and the mixture was extracted with EtOAc (3×10 mL).The combined organic phases were dried over MgSO₄ and evaporated to give2-[2,6-Bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-4-methyl-pentanoicacid as a white solid (0.2 g, 40%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.65(d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.72 (s, 2H), 4.24 (q, J=8.0Hz, 4H), 3.69 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.76-1.67 (m, 1H),1.60-1.52 (m, 1H), 0.96 (d, J=6.3 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃/TMS):δ 179.3, 155.4, 140.6, 135.3, 130.9, 129.6, 129.1, 124.5 (q, ³J_(CF)=4Hz), 124.2 (q, ¹J_(CF)=272 Hz), 122.9 (q, ¹J_(CF)=278 Hz), 119.8, 107.9,66.5 (q, ²J_(CF)=36 Hz), 49.7, 42.2, 25.9, 22.6, 22.3.

Example 24202-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionicacid

Step 1

4-Fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene

To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was addedsodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep thetemperature between 30 and 40° C. After the temperature had dropped to30° C., the reaction mixture was heated to 45-50° C. using an oil bathfor additional 16 h. After cooling, water (500 mL) and 2.5 NH₂SO₄(200-300 mL, for adjustment of pH to 5) were added and the organic layerwas separated. The water layer was extracted with EtOAc (2×300 mL). Thecombined organic layers were washed with saturated sodium chloridesolution (100 mL) and dried over magnesium sulfate. The solvent wasevaporated to give a yellow oil, which solidified after 30 min to give ayellowish solid (450.0 g, quantitative). The crude product was used inthe next step without purification. ¹H NMR (300 MHz, CDCl₃/TMS): δ8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). ¹³C NMR(75 MHz, CDCl₃/TMS): δ 165.0 (d, ¹J_(CF)=259.6 Hz), 152.3 (d,³J_(CF)=13.1 Hz), 128.2 (d, ³J_(CF)=11.9 Hz), 122.4 (d, ¹J_(CF)=273.4Hz), 110.1 (d, ²J_(CF)=22.5 Hz), 105.9 (q, ¹J_(CF)=242.6 Hz), 104.3 (d,²J_(CF)=26.1 Hz), 67.6 (q, ¹J_(CF)=36.7 Hz).

Step 2

[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid

Potassium hydroxide (>85%, 176 g, >2.67 mmol) was added to a solution of4-fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene (412 g, ˜90% purity,1.56 mmol) and diethyl malonate (503.0 g, 3.14 mmol) in DMSO (700 mL) inportions to keep the temperature at ˜40° C. The reaction mixture becamedeep red in color. The reaction mixture was stirred at 40° C. overnight.Monitoring was performed by TLC (EtOAc:Hept., 1:3).

Acetic acid (1 L) was added to the warm reaction mixture followed by amixture of concentrated sulfuric acid (325 mL) in water (1 L) in oneportion. A precipitate, which was formed initially, dissolved at the endof the addition. Effective stirring was required for this reaction. Thereaction mixture was heated at reflux overnight. The reaction mixturewas cooled to room temperature and EtOAc (1000 mL) and water (1000 mL)were added. The organic layer (bottom layer!) was separated. The aqueoussolution was extracted with EtOAc (500 mL), the organic phases werecombined, washed with water (3×2000 mL), brine (500 mL), and dried overMgSO₄ with charcoal. The solvent was evaporated and the solid residuewas washed by stirring with heptane/EtOAc (20:1, 500 mL). The solid wasfiltered and dried in vacuum. The yield of2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid was 256 g (65%).¹H NMR (300 MHz, CDCl₃/TMS): δ 7.80 (d, J=8.3 Hz, 1H), 7.25 (s, 1H),7.10 (d, J=8.3 Hz, 1H), 5.07 (s, 1H), 4.67 (q, J=8.2 Hz, 2H), 3.70 (s,2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 175.0, 151.5, 144.0, 140.3, 126.4,125.0, 122.2 (d, ¹J_(CF)=273.0 Hz), 118.0, 67.6 (q, ¹J_(CF)=36.0 Hz),42.5.

Step 3

[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]acetic acid methyl ester

Concentrated sulfuric acid (50 mL) was added slowly to a solution of2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid (180 g, 0.64mol) in MeOH (500 mL). The reaction mixture was stirred at roomtemperature overnight. The methanol was evaporated and EtOAc (500 mL)was added. The solution was washed with water (2×200 mL) and brine anddried over MgSO₄. The solvent was evaporated, the solid residue wasstirred with heptane (200 mL), and the solid was filtered. Yield 182.2 g(96%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.82 (d, J=8.7 Hz, 1H), 7.07-7.05(m, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.67 (s, 2H). ¹³C NMR (75MHz, CDCl₃/TMS): δ 170.1, 150.4, 141.2, 139.4, 125.9, 123.9, 122.6 (d,¹J_(CF)=277.6 Hz), 117.5, 67.6 (q, ¹J_(CF)=36.7 Hz), 52.4, 41.0.

Step 4

3-Cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionicacid methyl ester

[4-Nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid methyl ester (33g, 94.5 mmol) and (bromomethyl)cyclobutane (17 g, 114.1 mmol) were mixedin DMSO (50 mL) and KOH (6.4 g, 114.1 mmol) was added in portions over15 min. The reaction mixture was stirred for 16 h and water (100 mL) wasadded. The reaction mixture was extracted with EtOAc (3×50 mL). Thecombined organic phases were dried over MgSO₄ and evaporated to give acrude yellow oil, which was purified by silica gel gradient columnchromatography using Heptane-EtOAc (9:1-4:1) to give 15 g (40%) of theproduct as a yellow oil. (The synthesis was repeated with temperaturekept at 40° C. over 16 h to give the product in quantitative yield). ¹HNMR (300 MHz, CDCl₃/TMS): δ 7.86 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 2H),4.50 (q, J=7.7 Hz, 2H), 3.68 (s, 3H), 3.55 (t, J=7.3 Hz, 1H), 2.22-2.10(m, 2H), 2.03-1.75 (m, 5H), 1.70-1.55 (m, 2H). ¹³C NMR (75 MHz,CDCl₃/TMS): δ 172.9, 150.5, 146.4, 139.4, 126.0, 122.7, 122.6 (d,¹J_(CF)=277.6 Hz), 116.0, 67.5 (q, ¹J_(CF)=36.7 Hz), 52.3, 49.6, 40.7,33.9, 28.2, 27.9, 18.4.

Step 5

2-[4-Amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionicacid methyl ester

A solution of the3-cyclobutyl-2-[4-nitro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-propionicacid methyl ester (15 g, 36.0 mmol) in EtOH (150 mL) was hydrogenated at50 psi and 25° C. for 16 h in the presence of Pd—C catalyst (10%, 1.5g). On the next day, the catalyst was filtered off and the solventevaporated to give the crude product (12.3 g, 88%) as a yellow oil,which was used without purification for the next step. ¹H NMR (300 MHz,CDCl₃/TMS): δ 6.79-6.73 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 4.36 (q, J=8.3Hz, 2H), 3.80 (br s, 2H), 3.63 (s, 3H), 3.35 (t, J=7.7 Hz, 1H),2.20-1.86 (m, 4H), 1.85-1.70 (m, 3H), 1.67-1.51 (m, 2H). ¹³C NMR (75MHz, CDCl₃/TMS): δ 174.7, 146.7, 135.7, 129.1, 123.3 (d, ¹J_(CF)=277.6Hz), 122.7, 115.4, 112.2, 66.4 (q, ¹J_(CF)=35.4 Hz), 51.9, 48.9, 40.8,34.0, 28.3, 28.1, 18.5.

Step 6

2-[4-Amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionicacid methyl ester

To a solution of the2-[4-amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionicacid methyl ester (12.3 g, 31.8 mmol) in chloroform (150 mL) was addedN-bromosuccinimide (7 g, 39.3 mmol). The reaction mixture was stirred at25° C. for 16 h and a mixture of water and methylene chloride (100mL/100 mL) was added. The reaction mixture was extracted with methylenechloride (2×50 mL) and the organic phases were separated. The combinedorganic phases were dried over MgSO₄ and evaporated to give a crudeyellow oil, which was purified by a short silica gel columnchromatography eluting with heptane-EtOAc (4:1) to give the product(13.9 g, 94%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.06(d, J=1.1 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 4.37 (q, J=8.0 Hz, 2H), 4.21(br s, 2H), 3.64 (s, 3H), 3.31 (t, J=7.7 Hz, 1H), 2.20-1.89 (m, 4H),1.81-1.75 (m, 3H), 1.67-1.51 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ174.2, 144.6, 134.4, 128.9, 125.7, 123.0 (d, ¹J_(CF)=277.6 Hz), 110.9,108.7, 66.5 (q, ¹J_(CF)=36.0 Hz), 52.0, 48.6, 40.7, 33.9, 28.3, 28.0,18.5.

Step 7

2-[6-Amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionicacid methyl ester

To a solution of2-[4-amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionicacid methyl ester (13.8 g, 29.6 mmol) in DME (anhydrous, 100 mL) underargon atmosphere were added 4-trifluoromethylphenylboronic acid (6.8 g,35.8 mmol), CsF (11 g, 72.3 mmol), and Pd(PPh₃)₄ (3.4 g, 2.94 mmol). Thereaction mixture was refluxed for 18 h (oil bath, 100° C.). On the nextday, a mixture water and EtOAc (100 mL/100 mL) was added and the layerswere separated. The organic phase was dried over MgSO₄ and evaporated togive a crude yellow oil, which was purified by a short silica gel columnchromatography by use of Heptane-EtOAc (4:1) to give the product (14.7g, 94%) as a yellowish oil. ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.70 (d,J=8.2 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 6.78 (dd, J=9.6, 1.4 Hz, 2H),4.43 (q, J=8.0 Hz, 2H), 3.95 (br s, 2H), 3.66 (s, 3H), 3.39 (t, J=7.7Hz, 1H), 2.25-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.88-1.75 (m, 3H),1.69-1.52 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 174.6, 144.8, 133.1,129.2, 128.6, 126.3, 125.7 (q, ³J_(CF)=3.6 Hz), 123.8, 123.3 (q,¹J_(CF)=277.6 Hz), 111.4, 66.5 (q, ¹J_(CF)=35.4 Hz), 52.0, 49.0, 40.9,34.1, 28.3, 28.1, 18.5.

Step 8

2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionicacid methyl ester

To a solution of2-[6-amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionicacid methyl ester (14.7 g, 27.7 mmol) in a mixture of MeCN and H₂O (120mL/120 mL), concentrated HCl (25 mL) was added. The reaction mixture wascooled down to 0-5° C. and a solution of NaNO₂ (2.9 g, 42.0 mmol) inwater (3 mL) was added dropwise. The reaction mixture was stirred at0-5° C. for 40 min and CuCl (I) (27 g, 272.7 mmol) was added at once.The reaction mixture was heated at 50° C. for additional 3 h and thesolvent was evaporated. The reaction mixture was extracted with EtOAc(3×50 mL) and the combined organic phases were washed with water (200mL) and brine (100 mL). The organic phase was dried over MgSO₄ andevaporated to give the product (14.5 g, 95%) as a yellow oil. ¹H NMR(300 MHz, CDCl₃/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H),6.98 (dd, J=6.1, 1.6 Hz, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.48(t, J=7.7 Hz, 1H), 2.20-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.52 (m,2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 173.6, 153.5, 142.2, 141.0, 138.9,129.7, 125.0 (q, ³J_(CF)=3.6 Hz), 124.8, 124.0 (q, ¹J_(CF)=271.6 Hz),126.6 (q, ¹J_(CF)=278.8 Hz), 121.4, 114.0, 67.3 (q, ¹J_(CF)=35.4 Hz),52.2, 49.3, 40.8, 34.0, 28.3, 28.0, 18.5.

Step 9

2-[6-Chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionicacid

To a solution of the2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionicacid methyl ester (8.0 g, 14.5 mmol) in a mixture of the EtOH (100 mL)and H₂O (15 mL) was added potassium hydroxide (10 g, 178.5 mmol). Thereaction mixture was refluxed for 3 h and the solvent evaporated. Then,6 N HCl was added to adjust the pH to 3-5 and the mixture was extractedwith EtOAc (3×50 mL). The combined organic phases were dried over MgSO₄and evaporated to give2-[6-chloro-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionicacid as a white solid (7.0 g, 90%). ¹H NMR (300 MHz, CDCl₃/TMS): δ 7.70(d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 6.98 (s, 2H), 4.47 (q, J=8.0Hz, 2H), 3.49 (t, J=7.7 Hz, 1H), 2.27-2.13 (m, 2H), 2.06-1.73 (m, 5H),1.71-1.52 (m, 2H). ¹³C NMR (75 MHz, CDCl₃/TMS): δ 179.1, 153.6, 142.1,141.2, 138.0, 129.7, 125.0 (q, ³J_(CF)=3.6 Hz), 124.9, 124.0 (q,¹J_(CF)=262.5 Hz), 123.0 (q, ¹J_(CF)=277.6 Hz), 121.8, 114.3, 67.3 (q,¹J_(CF)=36.0 Hz), 49.3, 40.3, 33.9, 28.3, 28.0, 18.5.

Example 4152-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

Step 1

Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.076molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol). The mixturewas brought to reflux and sulfuryl chloride (6.8 ml 0.846 mol) dissolvedin DCM (50 mL) was slowly added under over 10 min. The reaction mixturewas refluxed further for 5 h, upon which the reaction mixture was pouredonto crushed ice and extracted with DCM (×2). The combined organiclayers were washed with 10% NaHCO₃ solution and water. The organic layerwas dried over Na₂SO₄, filtered and evaporated under vacuum to givecompound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6g).

Step 2

Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of compound ethyl2-(3-chloro-4-hydroxyphenyl)acetate (11 g, 51 mmol) in 200 ml of CCl₄,was slowly added bromine (8.22 g, 51 mmol) as a solution CCl₄ (100 ml)at 0° C. over a period of 30 min. The reaction mixture was stirred for afurther 30 min at 0° C. Upon which the reaction mixture was poured ontocrushed ice and extracted with DCM (2×100 mL). The combined organiclayers were washed with water followed by 10% sodium bisulfite solution,dried over Na₂SO₄ filtered and evaporated under reduced pressure to giveethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12.2 g) as a whitesolid in 80% yield. ¹HNMR (CDCl₃): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs,1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).

Step 3

Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (2 g, 6.8 mmol), potassiumcarbonate (2.35 g, 17.0 mmol) in dry DMF (20 mL), was slowly addedtrifluoro ethyl iodide (8.58 g, 4.0 mL, 40.8 mmol) at room temperature,the reaction mixture was slowly heated to 100° C. and heating wascontinued for 4 h. Upon which the reaction mixture was poured onto waterand extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with water, dried over Na₂SO₄ and evaporated under reducedpressure. Purification by column chromatography over silica gel(hexane/EtOAc) to gave compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g,30% yield). ¹HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q,2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m,1H); 1.24 (t, 3H), 0.92 (d, 6H);

Step 4

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate

A mixture of2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g,2.0 mmol), 4-trifluoromethyl phenylboronic acid (0.567 g, 3.0 mmol), Pd(PPh₃)₄ (0.231 g, 0.2 mmol), cesium fluoride (0.604 g, 4.0 mmol) in DME(10 ml) was stirred overnight at 100° C., upon which the precipitateswere removed by filtration. The filtrate was diluted with water andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with water followed by brine and dried over Na₂SO₄. The cruderesidue was purified by flash column chromatography to give ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.525 g, 73.6%) as an off white solid.

Step 5

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(1.0 g, 2.27 mmol) was dissolved in anhydrous DMF (80 mL), NaH (60% wt.in paraffin oil, 0.109 g, 2.72 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature, upon whichcyclopropyl methyl bromide (0.24 mL, 2.5 mmol) was added in a dropwisemanner at 0° C. The reaction mixture was stirred an additional 1 h at 0°C. upon which saturated NH₄Cl solution (10 mL) was added. The reactionmixture was extracted with EtOAc (3×50 mL) and the combined organicphases were washed with water (3×20 mL) and brine (20 mL), dried overNa₂SO₄, filtered and evaporated under reduced pressure to give colorlessoil, which was purified by flash column chromatography to yield compoundethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(0.68 g).

Step 6

2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

A mixture of ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(0.68 g, 0.4 mmol) and lithium hydroxide monohydrate (100 mg, 4.6 mmol)in a MeOH/THF/Water solvent mixture (15 ml/15 ml/15/ml) was stirred for3 h at room temperature. After completion of reaction, the volatileswere removed under reduced pressure. The residue was diluted with water,acidified with 5% HCl solution and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by Flash Column Chromatography to give2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid in 88% yield (0.4 g). ¹H-NMR (CDCl₃, 500 MHz): 7.72 (d, 2H); 7.65(d, 2H), 7.43 (s, 1H); 7.24 (s, 1H); 3.98 (q, 2H); 3.72 (t, 1H); 1.94(m, 1H), 1.78 (m, 1H); 0.71 (m, 1H), 0.46 (m, 2H), 0.02-0.19 (m, 2H).

Example 12691-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutanecarboxylic acid

Step 1

Ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(Trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(1.5 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and1,3-dibromopropane (0.757 g, 3.7 mmol) was added drop wise at 0° C. Thereaction mixture was stirred for an additional 1 h at 0° C. andsaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic phases werewashed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. Thevolatiles were removed under reduced pressure and the residue waspurified by flash column chromatography to yield compoundethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylate (400 mg).

Step 2

1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutanecarboxylic acid

A mixture ofethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylate (400 mg, 0.83 mmol) and lithium hydroxide monohydrate(0.2 g, 8.3 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10ml) was stirred for 3 h at room temperature. Upon completion of thereaction, the volatiles were removed under reduced pressure. The residuewas diluted with water, acidified with 5% HCl solution and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith water, dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by column chromatography to give1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutanecarboxylic acid in 88% yield (0.21 g). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d,2H); 7.65 (d, 2H), 7.39 (s, 1H); 7.26 (s, 1H); 3.98 (q, 2H); 2.86 (m,2H); 2.52 (m, 2H); 2.16 (m, 1H), 1.91 (m, 1H).

Example 4191-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentanecarboxylic acid

Step 1

Ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.8 g, 1.81 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.109 g, 4.5 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and 1,4-dibromobutane(0.432 g, 1.99 mmol) was added drop wise at 0° C. The reaction mixturewas stirred an additional 1 h at 0° C. upon which saturated NH₄Clsolution (10 mL) was added. The reaction mixture was extracted withEtOAc (3×20 mL) and the combined organic phases were washed with water(3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles wereremoved under reduced pressure and the residue was purified by flashcolumn chromatography to yield compound ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylate (400 mg) as a thick liquid.

Step 2

1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentanecarboxylic acid

A mixture of compound ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentane carboxylate (100 mg, 0.21 mmol) and lithium hydroxidemonohydrate (96 mg, 2.1 mmol) in a MeOH/THF/Water solvent mixture (5ml/5 ml 5/ml) was stirred for 3 h at room temperature. After completionof reaction, the volatiles were removed under reduced pressure. Theresidue was diluted with water, acidified with 5% HCl solution andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water, dried over Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified by Flash ColumnChromatography to give1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopentanecarboxylic acid (0.05 g). ¹H-NMR (CDCl₃, 500 MHz): 7.72 (d, 2H); 7.65(d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.68 (m, 2H); 1.94(m, 2H); 1.78 (m, 4H).

Example 32024-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylicacid

Step 1

Ethyl4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.4 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.163 g, 6.8 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and1-iodo-2-(2-iodoethoxy)ethane (1.2 g, 3.7 mmol) was added drop wise at0° C. The reaction mixture was stirred an additional 1 h at 0° C. andsaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic phases werewashed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. Thevolatiles were removed under reduced pressure and the residue waspurified by flash column chromatography to yield ethyl4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate(400 mg).

Step 2

4-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylicacid

A mixture of ethyl4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate(400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.188 g, 7.8mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirredfor 3 h at room temperature. After completion of reaction volatiles wereremoved under reduced pressure. Residue was diluted with water,acidified with 5% HCl solution and extracted with ethyl acetate (3×50mL). Combined organic layer was washed with water, dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedby Flash Column Chromatography to give4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylicacid (100 mg). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56(s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 3.61 (t, 2H); 2.53 (dd, 2H); 1.99(m, 2H).

Example 32031-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylicacid

Step 1

Ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and3,3-dimethyl-1,5-dibromopentane (0.322 g, 1.25 mmol) was added drop wiseat 0° C. The reaction mixture was stirred an additional 1 h at 0° C. andsaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic phases werewashed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄. Thevolatiles were removed under reduced pressure and the residue waspurified by flash column chromatography to yield compound ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate(230 mg).

Step 2

1-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylicacid

A mixture of compound ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate(200 mg, 0.37 mmol) and lithium hydroxide monohydrate (88 mg, 3.7 mmol)in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 hat room temperature. After completion of the reaction, the volatileswere removed under reduced pressure. The residue was diluted with water,acidified with 5% HCl solution and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with water, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by Flash Column Chromatography to give1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylicacid in 67% yield (150 mg). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65(d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.88(m, 2H); 1.41 (m, 4H), 0.98 (s, 3H), 0.91 (s, 3H).

Example 12701-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylic acid

Step 1

Ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and1,5-dibromopentane (0.19 g, 1.24 mmol) was added drop wise at 0° C. Thereaction mixture was stirred an additional 1 h at 0° C. and saturatedNH₄Cl solution (10 mL) was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the combined organic phases were washed withwater (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatileswere removed under reduced pressure and the residue was purified byflash column chromatography to yield compound ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate(0.37 g) as a thick liquid.

Step 2

1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylic acid

A mixture of ethyl1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate(0.37 g, 0.72 mmol) and lithium hydroxide monohydrate (0.174 g, 7.28mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) wasstirred for 3 h at room temperature. After completion of reactionvolatiles were removed under reduced pressure. The residue was dilutedwith water, acidified with 5% HCl solution and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Theresidue was purified by Flash Column Chromatography to give1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylic acid (0.25 g) as a white solid. ¹H-NMR (CDCl₃, 400 MHz): 7.72(d, 2H); 7.65 (d, 2H), 7.55 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48(dd, 2H); 1.52-1.81 (m, 6H); 1.33 (m, 2H).

Example 12715-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylicacid

Step 1

Ethyl5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-Spiro[2,3]hexane-5-carboxylate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.136 g, 3.4 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and1,1-bis(bromomethyl)cyclopropane (0.482 g, 1.4 mmol, for preparation seeJ. Org. Chem. 1993, 58, 4122-26) was added drop wise at 0° C. Thereaction mixture was stirred an additional 1 h at 0° C. and saturatedNH₄Cl solution (10 mL) was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the combined organic phases were washed withwater (3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatileswere removed under reduced pressure and the residue was purified byflash column chromatography to yield compound ethyl5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate(150 mg) as a low melting solid.

Step 2

5-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylicacid

A mixture of ethyl5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate(0.5 g, 0.9 mmol) and lithium hydroxide monohydrate (0.415 g, 9.88 mmol)in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for3 h at room temperature. After completion of reaction volatiles wereremoved under reduced pressure. Residue was diluted with water,acidified with 5% HCl solution and extracted with ethyl acetate (3×50mL). The combined organic layer was washed with water, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by Flash Column Chromatography to give5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylicacid (0.29 g). ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41(s, 1H); 7.21 (s, 1H); 3.98 (q, 2H); 2.95 (d, 2H); 2.75 (d, 2H), 0.58(t, 2H), 0.48 (t, 2H).

Example 12682-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoicacid

Step 1

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.6 g, 0.49 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.039 g, 1.69 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and cyclobutylmethylbromide (0.223 g, 1.49 mmol) was added drop wise at 0° C. The reactionmixture was stirred an additional 1 h at 0° C. and saturated NH₄Clsolution (10 mL) was added. The reaction mixture was extracted withEtOAc (3×20 mL) and the combined organic phases were washed with water(3×20 mL) and brine (20 mL), and dried over MgSO₄ The volatiles wereremoved under reduced pressure and the residue was purified by flashcolumn chromatography to yield ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate(0.25 g) as a colorless liquid.

Step 2

2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoicacid

A mixture of ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate(0.25 g, 0.49 mmol) and lithium hydroxide monohydrate (0.206 g, 4.9mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) wasstirred for 3 h at room temperature. After completion of reactionvolatiles were removed under reduced pressure. Residue was diluted withwater, acidified with 5% HCl solution and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with water, driedover Na₂SO₄, filtered and evaporated under reduced pressure. The residuewas purified by Flash Column Chromatography to give2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoicacid (0.106 g) as a white solid. ¹H-NMR (CDCl₃, 400 MHz): 7.72 (d, 2H);7.65 (d, 2H), 7.41 (s, 1H); 7.18 (s, 1H); 3.98 (q, 2H); 3.51 (t, 1H);2.15-2.28 (m, 2H); 1.55-2.15 (m, 7H).

Example 12722-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylaceticacid

Step 1

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.8 g, 1.8 mmol) was dissolved in anhydrous DMF (40 mL), NaH (60% wt.in paraffin oil, 0.052 g, 2.18 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and cyclopentylbromide (0.298 g, 1.99 mmol) was added drop wise at 0° C. The reactionmixture was stirred an additional 1 h at 0° C. and saturated NH₄Clsolution (10 mL) was added. The reaction mixture was extracted withEtOAc (3×50 mL) and the combined organic phases were washed with water(3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles wereremoved under reduced pressure and the residue was purified by flashcolumn chromatography to yield compound ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate(0.4 mg) as a thick liquid.

Step 2

2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylaceticacid

A mixture of ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate(400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.330 g, 7.87mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) wasstirred for 3 h at room temperature. After completion of reactionvolatiles were removed under reduced pressure. The residue was dilutedwith water, acidified with 5% HCl solution and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Theresidue was purified by Flash Column Chromatography to give2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylaceticacid (0.08 g). ¹H-NMR (CDCl₃, 400 MHz): 12.5 (s, 1H), 7.84 (d, 2H); 7.70(d, 2H), 7.55 (s, 1H); 7.35 (s, 1H); 4.22 (q, 2H); 3.3.35 (d, 1H); 1.82(m, 1H); 1.18-1.68 (m, 7H); 1.08 (m, 1H).

Example 32042-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoicacid

Step 1

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt.in paraffin oil, 0.039 g, 1.36 mmol) was added at 0° C. The reactionmixture was stirred for 30 min at room temperature and cyclopentylbromide (0.283 g, 1.49 mmol) was added drop wise at 0° C. The reactionmixture was stirred an additional 1 h at 0° C. and saturated NH₄Clsolution (10 mL) was added. The reaction mixture was extracted withEtOAc (3×20 mL) and the combined organic phases were washed with water(3×20 mL) and brine (20 mL), and dried over MgSO₄. The volatiles wereremoved under reduced pressure and the residue was purified by flashcolumn chromatography to yield compound ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate(0.29 g) as a colorless liquid.

Step 2

2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoicacid

A mixture of ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate(400 mg, 0.719 mmol) and lithium hydroxide monohydrate (0.306 g, 7.29mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) wasstirred for 3 h at room temperature. After completion of reactionvolatiles were removed under reduced pressure. The residue was dilutedwith water, acidified with 5% HCl solution and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Theresidue was purified by Flash Column Chromatography to give2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoicacid (0.1 g). ¹H-NMR (CDCl₃, 400 MHz): 7.55-7.78 (m, 4H); 7.42 (s, 1H),7.18 (s, 1H); 6.92-7.16 (m, 4H); 3.98 (q, 2H); 3.84 (t, 1H); 3.41 (dd,1H), 3.02 (dd, 1H).

Example 19052-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoicacid

Step 1

2-(Cyclopropylmethoxy)-4-fluoro-1-nitrobenzene

Cyclopropyl methanol (15 g, 207 mmol) was added to a stirred suspensionof NaH (60% in mineral oil, 8.37 g) in 200 mL THF over a period of 15min at 0° C. under an atmosphere of nitrogen. The reaction mixture wasallowed to warm to room temperature and stirred for 1 h at RT. Themixture was cooled to 0° C. and a solution of2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added ina drop wise manner. The reaction mixture was stirred at 0° C. for 2 hand then poured onto ice water. The mixture was extracted with ethylacetate (3×100 mL). The combined organic layers were dried over MgSO₄and concentrated under reduced pressure to give 22.0 g of2-(cyclopropylmethoxy)-4-fluoro-1-nitrobenzene as an orange oil (86%).

Step 2

Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate

Diethyl malonate (9.8 g, 1.1 eq) was added to a stirred suspension ofsodium hydride (60% in mineral oil, 2.09 g) in DMF (88 mL) over 15 min.at 0° C. under nitrogen. The reaction mixture was allowed to warm toroom temperature and stirred for 1 h. A solution of2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq) in DMF (88 mL)was added drop wise at 0° C., and the reaction mixture was heated to100° C. for 3 h. The reaction mixture was allowed to cool to roomtemperature, poured into ice water and extracted with EtOAc (3×100 mL).The combined organic phases were washed with water (3×100 mL) and brine(100 mL), dried (MgSO₄) and filtered. Evaporation of the volatiles underreduced pressure gave 10.0 g of crude product which was purified bychromatography over silica gel (hexane/EtOAc) gave of diethyl2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (7.0 g). ¹H-NMR (CDCl₃,200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3 (m, 1H), 1.3 (t, 6H), 3.96 (d,2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02 (d, 1H), 7.18 (s, 1H), 7.81 (d,2H).

Step 3

2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid

Compound diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (10 g)was dissolved in 100 mL ethanol and cooled to 0° C., NaOH solution (4eq) was added slowly to the reaction mixture for about 15 min. Thereaction mixture was heated gently up to 60° C. for 5 h. Progress of thereaction was monitored by TLC analysis. After complete conversion ofstarting material solvent was evaporated under reduced pressure, residuedissolved in H₂O, acidified with 6N HCl to pH-2. Filtered the solidmaterial washed with water, dried under reduced pressure to give2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5 g) as a yellowsolid. ¹H-NMR (CDCl₃, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.28 (m,1H), 3.71 (s, 2H), 4.01 (d, 2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d,1H).

Step 4

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate

2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid (40 g, 143 mmol) wasdissolved in 20% EtOH—HCl solution (200 ml) and refluxed for 3 h toconvert the starting material to ester. The volatiles were removed underreduced pressure and the residue was extracted with ethyl acetate (×2).The combined organic extracts were washed with water, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude material waspurified by re crystallization to ethyl2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (38 g) as pale yellowsolid.

Step 5

Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of compound ethyl2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100mL), Pd(OH)₂ (2 g) was added and the mixture was reduced under an H₂atmosphere for 6 h at room temperature. The mixture was filtered a padof Celite™ washing with MeOH. The combined filtrates were concentratedunder reduced pressure to yield ethyl2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (7.5 g) as a thickliquid. ¹H-NMR (CDCl₃, 200 MHz): 0.38 (m, 2H), 0.61 (m, 2H), 1.23 (m,1H), 1.23 (t, 3H), 3.51 (s, 2H), 3.80 (d, 2H), 4.16 (q, 2H), 6.72 (m,3H).

Step 6

Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dryCCl₄ (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reactionmixture was allowed to stir for 3 h at room temperature. The reactionmixture was diluted with water and extracted with DCM (2×50 mL). Thecombined organic layers were dried over Na₂SO₄, filtered and thevolatiles removed in vacuo. The crude reaction mixture was purified bycolumn chromatography to give ethyl2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as ayellow solid.

Step 7

Ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate

Ethyl-2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)-acetate (2.5 g,10.0 mmol) was dissolved in a mixture of EtOH/H₂O/H₂SO₄ (96%) 200 mL/400mL/10 mL at 0° C. A solution of NaNO₂ (3.2 g, 1.16 eq) in water (40 mL)was added drop wise at 0° C., and the reaction mixture was stirred for40 min at the same temperature. A solution of KI (30 g, 30.1 mmol) inwater (80 mL) was added drop wise at 0° C. The reaction mixture washeated to 50° C. for 2.5 h upon which the volatiles were removed underreduced pressure. The reaction mixture was extracted with EtOAc (3×50mL), and the combined organic layers were washed with 10% sodiumthiosulfate (2×50 mL), water (300 mL) and brine (300 mL). The organicsolution was dried over Na₂SO₄ and concentrated under reduced pressureto give a crude black oil which was purified by chromatography oversilica gel (hexane/EtOAc) to give the product ethyl2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate as a yellow oil(8.7 g).

Step 8

Ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate

A mixture of compound ethyl2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 14mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28g, 1.84 mmol) and Pd (PPh₃)₄ (0.410 g, 0.4 mmol) in 75 mL anhydrous1,2-dimethoxy ethane was refluxed for 8 h under argon. The reactionmixture was cooled to RT and 75 mL of EtOAc and 75 mL of water wereadded. The organic phase was separated, dried over NaSO₄, filtered andconcentrated under reduced pressure to give a yellow oil. The oil waspurified by chromatography over silica gel (hexane/EtOAc) to give ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate(4.6 g) as a yellow oil. ¹H-NMR (CDCl₃, 200 MHz): 0.41 (m, 2H), 0.62 (m,2H), 1.22 (t, 3H), 1.23 (m, 1H), 3.58 (s, 2H), 3.89 (d, 2H), 4.17 (q,2H), 6.96 (m, 2H), 7.31 (s, 1H), 7.64 (m, 4H).

Step 9

2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoicacid

Ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate(1.1 g, 2.4 mmol) was dissolved in 10 mL anhydrous DMF and NaH (60% wt.in oil, 0.9 g) was added at 0° C. The reaction mixture was stirred for0.5 h at 25° C. and cyclopropyl methyl bromide (1.25 mL) was added dropwise at 0° C. The reaction mixture was stirred for an additional 1 h at0° C. upon which saturated NH₄Cl solution (10 mL) was added. Thereaction mixture was extracted with EtOAc (3×20 mL) and the combinedorganic phases were washed with water (3×20 mL) and brine (20 mL), anddried over MgSO₄, filtered and the volatiles removed under reducedpressure to give 0.85 g of a colorless oil. The oil was dissolved in 10mL of EtOH/H₂O (9:1, v/v) and (1.0 g) LiOH added. The reaction mixturewas refluxed for 5 h and concentrated under reduced pressure. Water (10mL) was added and the reaction mixture was extracted with EtOAc (3×10mL). The combined organic phases were dried over MgSO₄ and evaporatedunder reduced pressure. Purification by column chromatography oversilica gel (hexane/EtOAc 9:1) gave2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3cyclopropylpropanoic acid (0.42 g) as a white solid, L-21-1 (56%). ¹HNMR (300 MHz, CDCl₃): δ 7.65 (d, 2H), 7.38 (d, 2H), 7.08 (s, 1H), 6.83(s, 1H), 3.75 (d, 2H), 3.62 (t, 1H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84(m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).

Example 19081-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclobutanecarboxylicacid

Ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate(0.5 g,) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil,0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for0.5 h at 25° C. and 1,3-dibromopropane (1.5 mL) was added drop wise at0° C. The reaction mixture was stirred at 0° C. for 1 h and upon whichsaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic phases werewashed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄,filtered and concentrated under reduced pressure to give 240 mg of acolorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, v/v) and0.42 g LiOH added. The reaction mixture was refluxed for 5 h andconcentrated under reduced pressure. Water (10 mL) was added and thereaction mixture was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified via column chromatographyover silica gel (hexane/EtOAc 9:1) to give1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclobutanecarboxylicacid (0.210 g) as a white solid (52% yield). ¹HNMR (300 MHz, CDCl₃): δ7.68 (d, 2H), 7.41 (d, 2H), 7.06 (s, 1H), 6.89 (s, 1H), 3.78 (d, 2H),2.88 (m, 2H), 2.58 (m, 2H), 2.16 (m, 1H), 1.97 (m, 1H), 1.03 (m, 1H),0.46 (m, 2H), 0.18 (m, 2H).

Example 19091-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclopentanecarboxylicacid

Ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate(0.5 g) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil,0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for0.5 h at 25° C. and 1,4-dibromobutane (0.24 g) was added drop wise at 0°C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Clsolution (10 mL) was added. The reaction mixture was extracted withEtOAc (3×20 mL) and the combined organic phases were washed with water(3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered andconcentrated under reduced pressure to give 380 mg of colorless oil. Theoil was dissolved in 10 mL of EtOH/H₂O (9:1, vvl) and 1.0 g LiOH added.The reaction mixture was refluxed for 5 h and concentrated under reducedpressure. Water (10 mL) was added and the reaction mixture was extractedwith EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄filtered and concentrated under reduced pressure. Purification by columnchromatography over silica gel (hexane/EtOAc 9:1) gave1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-cyclopentanecarboxylicacid (0.210 g) as a white solid (60%). ¹H NMR (500 MHz, CDCl₃): δ 7.68(d, 2H), 7.41 (d, 2H), 7.16 (s, 1H), 6.91 (s, 1H), 3.78 (d, 2H), 2.66(m, 2H), 1.97 (m, 2H), 1.79 (m, 4H), 1.03 (m, 1H), 0.46 (d, 2H), 0.18(d, 2H).

Example 24912-(6-Chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

Step 1

Ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol)was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.475 g, 19.7mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at25° C. and cyclopropylmethyl bromide (2.67 g, 19.7 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h andsaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic phases werewashed with water (3×20 mL) and brine (20 mL), dried over MgSO₄,filtered and concentrated under reduced pressure to give ethyl3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4 g) asa colorless oil.

Step 2

Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4.0 g),in dry MeOH (100 mL), Pd(OH)₂ (2 g) was added and the mixture wasreduced under an atmosphere of H₂ for 6 h at room temperature. Thereaction mixture was filtered through a pad of Celite™ washing withMeOH. The combined filtrates were concentrated under reduced pressure toyield ethyl2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (3.5 g)as a thick liquid.

Step 3

Ethyl 2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl2-(4-amino-3-(cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (3.0 g,9.8 mmol) in dry CHCl₃ (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C.The reaction mixture was allowed to stir for 3 h at room temperature.The reaction mixture was diluted with water and extracted with DCM (2×50mL). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude reaction mixture waspurified by column chromatography to yield the ethyl2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (1.5 g) as a yellow solid.

Step 4

Ethyl2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of ethyl2-(4-amino-3-bromo-5-(Cyclopropylmethoxy)phenyl)-3-cyclopropylpropanoate (2.8 g, 7.2 mmol), 4-trifluoromethylphenylboronic acid (2.05g, 18.8 mmol), CsF (2.19 g, 14.5 mmol) and Pd (PPh₃)₄ (0.837 g, 0.72mmol) in 30 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h underargon. The reaction mixture was cooled to RT, and 75 mL of EtOAc and 75mL of water were added. The organic phase was separated, dried overNaSO₄, filtered and concentrated under reduced pressure to give a yellowoil. The oil was purified by chromatography over silica gel(hexane/EtOAc) to give ethyl2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(2.5 g) as a yellow oil.

Step 5

Ethyl2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 30 mL/30 mL/2mL at 0° C. A solution of NaNO₂ (0.200 g, 2.9 mmol) in water (10 mL) wasadded drop wise at 0° C., and the reaction mixture was stirred for 40min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) inwater (10 mL) was added drop wise at 0° C. The reaction mixture washeated to 90° C. for 2.0 h and the mixture was concentrated underreduced pressure. The reaction mixture was extracted with EtOAc (3×50mL), the combined organic layers were washed with water (50 mL) followedby brine (50 mL), was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a crude black oil. The oil was purified bychromatography over silica gel (hexane/EtOAc) to give ethyl2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(1.1 g) as a yellow oil.

Step 6

2-(6-Chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(80 mg) was dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 57mg LiOH added. The reaction mixture was stirred at room temperature for5 h and then concentrated under reduced pressure. Water (10 mL) wasadded and the reaction mixture was extracted with EtOAc (3×10 mL). Thecombined organic phases were dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by column chromatography oversilica gel (hexane/EtOAc 9:1) gave compound2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid (45 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.71 (d, 2H),7.54 (d, 2H), 6.95 (d, 1H), 6.87 (s, 1H), 3.97 (d, 2H), 3.64 (t, 1H),2.55 (m, 2H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H),0.16 (m, 4H).

Example 24941-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylicacid

Step 1

Ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol)was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 1.43 g, 35.9mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at25° C. and 1,3-dibromopropane (1.91 mL, 17.9 mmol) was added drop wiseat 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturatedNH₄Cl solution (10 mL) was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the combined organic phases were washed withwater (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to give ethyl1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g)as a colorless oil.

Step 2

Ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g),in dry MeOH (100 mL), Pd(OH)₂ (1.2 g) was added and the reaction mixturewas reduced under an atmosphere of H₂ for 6 h at room temperature. Thereaction mixture was filtered through a pad of Celite™ washing withMeOH. The combined filtrates were concentrated under reduced pressure toyield ethyl1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g)as a thick liquid.

Step 3

Ethyl1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g,8.3 mmol) in dry CHCl₃ (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C.The reaction mixture was allowed to stir for 3 h at room temperature.The reaction mixture was diluted with water, extracted with DCM (2×50mL), the combined organic extracts were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude reaction mixture waspurified by column chromatography to yield ethyl1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate(1.5 g) as a yellow solid.

Step 4

Ethyl1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of ethyl1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate(0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh₃)₄ (0.1 g, 0.08 mmol) in 10mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. Thereaction mixture was cooled to RT and 25 mL of EtOAc and 75 mL of waterwere added. The organic phase was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a yellow oil. The oilwas purified by chromatography over silica gel (hexane/EtOAc) to giveethyl1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate(0.290 g) as a yellow oil.

Step 5

Ethyl1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

Ethyl1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate(0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 10 mL/10mL/4 mL at 0° C. A solution of NaNO₂ (0.066 g, 0.96 mmol) in water (2mL) was added drop wise at 0° C., and the reaction mixture was stirredfor 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixturewas heated to 70° C. for 1 h and the solvent was evaporated underreduced pressure. The reaction mixture was extracted with EtOAc (3×50mL), and the combined organic layers were washed with water (50 mL)followed by brine (50 mL). The solution was dried over Na₂SO₄, filteredand concentrated to give crude black oil which was purified bychromatography over silica gel (hexane/EtOAc) to give ethyl1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate(0.110 g) as yellow oil.

Step 6

1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylicacid

Ethyl1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate(0.1 g) dissolved in MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 70 mg LiOHadded. The reaction mixture was stirred at room temperature for 5 h andconcentrated under reduced pressure. Water (10 mL) was added and thereaction mixture was extracted with EtOAc (3×10 mL). The combinedorganic extracts were dried over MgSO₄, filtered and evaporated underreduced pressure. Purification by column chromatography over silica gel(hexane/EtOAc 9:1) gave1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylicacid (75 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.71 (d, 2H),7.54 (d, 2H), 6.86 (s, 1H), 6.85 (s, 1H), 3.97 (d, 2H), 2.85 (m, 2H),2.54 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H), 1.35 (t, 1H), 0.47 (m, 2H),0.41 (m, 2H).

Example 24951-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylicacid

Step 1

Ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (0.5 g) wasdissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol)was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C.and 1,4-dibromobutane (0.24 g, mmol) was added drop wise at 0° C. Thereaction mixture was stirred at 0° C. for 1 h and saturated NH₄Clsolution (10 mL) was added. The reaction mixture was extracted withEtOAc (3×20 mL) and the combined organic phases were washed with water(3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered andconcentrated under reduced pressure to give ethyl1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (380 mg)as a colorless oil.

Step 2

Ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (10 g),in dry MeOH (100 mL) Pd (OH)₂ (2 g) was added and the mixture wasreduced under an atmosphere of H₂ for 6 h at room temperature. Themixture was filtered through a pad of Celite™, washing with MeOH. Thecombined filtrates were concentrated under reduced pressure to yieldethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate(7.5 g) as a thick liquid.

Step 3

Ethyl1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (1.2 g,4.0 mmol) in dry CCl₄ (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0°C. The reaction mixture was allowed to stir for 3 at room temperature tocomplete the reaction. The reaction mixture was diluted with water,extracted with DCM (2×50 mL), the combined organic extracts were driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudereaction mixture was purified by column chromatography to yield ethyl1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate(920 mg) as a yellow solid.

Step 4

Ethyl1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

A mixture of ethyl1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate(5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol),CsF (0.28 g, 1.84 mmol) and Pd (PPh₃)₄ (0.410 g, 0.4 mmol) in 75 mLanhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. Thereaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water wereadded. The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yellow oil. The oil was purifiedby chromatography over silica gel (hexane/EtOAc) to give ethyl1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate(4.6 g) as a yellow oil.

Step 5

Ethyl1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

Ethyl1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate(1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 30 mL/30 mL/2mL at 0° C. A solution of NaNO₂ (0.200 g, 2.9 mmol) in water (10 mL) wasadded drop wise at 0° C., and the reaction mixture was stirred for 40min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) inwater (10 mL) was added drop wise at 0° C. The reaction mixture washeated to 90° C. for 2.0 h and the solvent was evaporated. The reactionmixture was extracted with EtOAc (3×50 mL), and the combined organiclayers were washed with water (50 mL) followed by brine (50 mL). Thesolution was dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a crude black oil. The oil was purified bychromatography over silica gel (hexane/EtOAc) to give ethyl1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylateas yellow oil (1.1 g).

Step 6

1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylicacid

Ethyl1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate(80 mg) dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 57 mgLiOH added. The reaction mixture was stirred at room temperature for 5 hand concentrated under reduced pressure. Water (10 mL) was added and thereaction mixture was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried over MgSO₄, filtered and concentrated underreduced pressure. Purification by column chromatography over silica gel(hexane/EtOAc 9:1) gave1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid (45 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.68(d, 2H), 7.55 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 3.97 (d, 2H), 2.64(m, 2H), 1.95 (m, 2H), 1.77 (m, 4H), 1.21 (m, 1H), 0.45 (m, 2H), 0.18(m, 2H);

Example 24192-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

Step 1

Ethyl3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (2 g, 6.5 mmol)was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.171 g, 7.1mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at25° C. and cyclopropylmethyl bromide (0.967 g, 7.16 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h andsaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic phases werewashed with water (3×20 mL) and brine (20 mL), dried over MgSO₄,filtered and concentrated under reduced pressure to give ethyl3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate(1.05 g) as a colorless oil.

Step 2

Ethyl2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate (1.0g), in dry MeOH (100 mL) Pd(OH)₂ (500 mg) was added and the mixture wasreduced under an atmosphere of H₂ for 6 h at room temperature. Themixture was filtered off through a pad of Celite™, washing with MeOH.The combined filtrates were concentrated under reduced pressure to giveethyl2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9g) as a thick liquid.

Step 3

Ethyl2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9g, 2.7 mmol) in dry CHCl₃ (50 mL), NBS (0.412 g, 2.3 mmol) was added at0° C. The reaction mixture was allowed to stir for 3 h at roomtemperature to complete the reaction. The reaction mixture was dilutedwith water, extracted with DCM (2×50 mL), the combined organic solventswas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The crude reaction mixture was purified by column chromatography to giveethyl2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(1.02 g) as a yellow solid.

Step 4

Ethyl2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of ethyl2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(1.1, 3.3 mmol), 4-trifluoromethylphenylboronic acid (1.26 g, 6.7 mmol),CsF (1.26 g, 8.3 mmol) and Pd (PPh₃)₄ (0.38 g, 0.33 mmol) in 50 mLanhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. Thereaction mixture was cooled, and 50 mL of EtOAc and 50 mL of water wereadded. The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a yellow oil. The oil waspurified by chromatography over silica gel (hexane/EtOAc) to give ethyl2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(0.85 g, 82% yield) as a white solid.

Step 5

Ethyl2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate

Ethyl2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(0.85 g, 1.78 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 15 mL/15mL/2 mL at 0° C. A solution of NaNO₂ (0.185 g, 2.68 mmol) in water (2mL) was added drop wise at 0° C., and the reaction mixture was stirredfor 40 min, at the same temperature. A solution of CuCl (1.8 g, 17.8mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixturewas heated to 90° C. for 2 h. The reaction mixture was extracted withEtOAc (3×50 mL), and the combined organic layers were washed with water(50 mL) followed by brine (50 mL). The solution was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give an oil. The oilwas purified by chromatography over silica gel (hexane/EtOAc) to giveethyl2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(0.528 g) as a yellow oil.

Step 6

2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoicacid

The ethyl2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate(500 mg, 1.01 mmol) dissolved in 20 mL of MeOH/THF/H₂O (10 mL/10 mL/5mL) and LiOH (57 mg) was added. The reaction mixture was stirred at roomtemperature for 5 h and concentrated under reduced pressure. Water (10mL) was added and the reaction mixture was extracted with EtOAc (3×10mL). The combined organic phases were dried over MgSO₄, filtered andconcentrated under reduced pressure. Purification by columnchromatography over silica gel (hexane/EtOAc 9:1) gave2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclopropylpropanoicacid (250 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.72 (d, 2H),7.54 (d, 2H), 7.02 (d, 2H), 4.44 (q, 2H), 3.72 (t, 1H), 1.92 (m, 1H),1.79 (m, 1H), 1.08 (m, 1H), 0.66 (m, 1H), 0.44 (m, 2H), 0.16 (m, 2H).

Example 2422 Ethyl1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

Step 1

Ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (3 g, 9.7 mmol)was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.514 g, 10.7mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at25° C. and 1,3-dibromopropane (1.03 mL, 9.7 mmol) was added drop wise at0° C. The reaction mixture was stirred at 0° C. for 1 h and saturatedNH₄Cl solution (10 mL) was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the combined organic phases were washed withwater (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to give ethyl1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900mg) as a colorless oil.

Step 2

Ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (900mg), in dry MeOH (50 mL), Pd(OH)₂ (400 mg) was added and the mixturereduced under an atmosphere of H₂ for 6 h at room temperature. Themixture was filtered through a pad of Celite™ washing with MeOH, thecombined filtrates were concentrated under reduced pressure to yieldethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(800 mg) as a thick liquid.

Step 3

Ethyl1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.4g, 8.3 mmol) in dry CHCl₃ (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0°C. The reaction mixture was allowed to stir for 3 hat room temperatureto complete the reaction. The reaction mixture was diluted with water,extracted with DCM (2×50 mL), the combined organic solvents were driedover Na₂SO₄, filtered and concentrated under educed pressure. The crudereaction mixture was purified by column chromatography to give ethyl1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(1.5 g) as a yellow solid.

Step 4

Ethyl1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of ethyl1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh₃)₄ (0.1 g, 0.08 mmol) in 10mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. Thereaction mixture was cooled, and 25 mL of EtOAc and 75 mL of water wereadded. The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a yellow oil. The oil waspurified by chromatography over silica gel (hexane/EtOAc) to give ethyl1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate(0.290 g) as a yellow oil.

Step 5

Ethyl1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate

Ethyl1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate(0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 10 mL/10mL/4 mL at 0° C. A solution of NaNO₂ (0.066 g, 0.96 mmol) in water (2mL) was added drop wise at 0° C., and the reaction mixture was stirredfor 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixturewas heated to 70° C. for 1 h and the solvent was evaporated. Thereaction mixture was extracted with EtOAc (3×50 mL), and the combinedorganic layers were washed with water (50 mL) followed by brine (50 mL).The solution was dried over Na₂SO₄, filtered and concentrated to giveoil. The oil was purified by chromatography over silica gel(hexane/EtOAc) to give ethyl1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylateas a yellow oil (0.110 g).

Step 6

1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylicacid

Ethyl1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate(0.1 g) dissolved in MeOH/THF/H₂O (10 mL/10 mL/5 mL) and 70 mg LiOHadded. The reaction mixture was stirred at room temperature for 5 h andconcentrated under reduced pressure. Water (10 mL) was added and thereaction mixture was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried over MgSO₄, filtered and evaporated underreduced pressure. Purification by column chromatography over silica gel(hexane/EtOAc 9:1) gave1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylicacid (75 mg) of the product as a white solid. ¹H-NMR (500 MHz, CDCl₃):7.74 (d, 2H), 7.53 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 4.43 (q, 2H),2.88 (m, 2H), 2.54 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H)

Example 24231-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylicacid

Step 1

Ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (0.5 g, mmol)was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g,mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at25° C. and 1,4-dibromobutane (0.24 g, mmol) was added drop wise at 0° C.The reaction mixture was stirred at 0° C. for 1 h and saturated NH₄Clsolution (10 mL) was added. The reaction mixture was extracted withEtOAc (3×20 mL) and the combined organic phases were washed with water(3×20 mL) and brine (20 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure to give ethyl1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (380mg) as a colorless oil.

Step 2

Ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (10g), in dry MeOH (100 mL) Pd(OH)₂ (2 g) was added and reduced under anatmosphere of H₂ for 6 h at room temperature. The mixture was filteredthrough a pad of Celite™ washing with MeOH. The combined filtrates wereconcentrated under reduced pressure to yield ethyl1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (7.5g) as a thick liquid.

Step 3

Ethyl1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2g, 4.0 mmol) in dry CCl₄ (60 mL), NBS (0.427 g, 3.2 mmol) was added at0° C. The reaction mixture was allowed to stir for 3 h at roomtemperature. The reaction mixture was diluted with water, extracted withDCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude reactionmixture was purified by column chromatography to give ethyl1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate(920 mg) as a yellow solid.

Step 4

Ethyl1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

A mixture of ethyl1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate(5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol),CsF (0.28 g, 1.84 mmol) and Pd(PPh₃)₄ (0.410 g, 0.4 mmol) in 75 mLanhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. Thereaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water wereadded. The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yellow oil. The oil was purifiedby chromatography over silica gel (hexane/EtOAc) to give ethyl1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate(4.6 g) as a yellow oil.

Step 5

Ethyl1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate

Ethyl1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate(1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 30 mL/30 mL/2mL at 0° C. A solution of NaNO₂ (0.200 g, 2.9 mmol) in water (10 mL) wasadded drop wise at 0° C., and the reaction mixture was stirred for 40min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) inwater (10 mL) was added drop wise at 0° C. The reaction mixture washeated to 90° C. for 2.0 h and the solvent was evaporated. The reactionmixture was extracted with EtOAc (3×50 mL), and the combined organiclayers were washed with water (50 mL) followed by brine (50 mL). Thesolution was dried over Na₂SO₄, filtered and concentrated under reducedpressure to give an oil. The oil was purified by chromatography oversilica gel (hexane/EtOAc) to give the ethyl1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (1.1 g) as yellow oil.

Step 6

1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylicacid

The ethyl1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5mL) and 57 mg LiOH added. The reaction mixture was stirred at roomtemperature for 5 h and concentrated under reduced pressure. Water (10mL) was added and the reaction mixture was extracted with EtOAc (3×10mL). The combined organic phases were dried over MgSO₄, filtered andconcentrated under reduced pressure. Purification by columnchromatography over silica gel (hexane/EtOAc 9:1) gave1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylic acid (45 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.74(d, 2H), 7.55 (d, 2H), 7.08 (s, 1H), 4.44 (q, 2H), 2.66 (m, 2H), 1.98(m, 2H), 1.78 (m, 4H).

Example 24182-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate

Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (4 g, 16.2mmol) was dissolved in 50 mL anhydrous DMF and NaH (60% wt. in oil,0.846 g, 21.1 mmol) was added at 0° C. The reaction mixture was stirredfor 0.5 h at 25° C. and isobutyl bromide (2.12 mL, 19.5 mmol) was addeddrop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h andsaturated NH₄Cl solution was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the combined organic phases were washed withwater (3×20 mL) and brine (20 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to give ethyl4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g)as a colorless oil.

Step 2

Ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g),in dry MeOH (100 mL), Pd(OH)₂ (500 mg) was added and the mixture reducedunder an atmosphere of H₂ for 6 h at room temperature. The mixture wasfiltered through a pad of Celite™ washing with MeOH. The combinedfiltrates were concentrated under reduced pressure to give ethyl2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.2 g)as a thick liquid.

Step 3

Ethyl2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.750 g,2.2 mmol) in dry CHCl₃ (100 mL), NBS (0.320 g, 1.8 mmol) was added at 0°C. The reaction mixture was allowed to stir for 3 h at room temperature.The reaction mixture was diluted with water, extracted with DCM (2×50mL), the combined organic solvents was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude reaction mixture waspurified by column chromatography to give ethyl2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(700 mg) as a yellow solid.

Step 4

Ethyl2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

A mixture of ethyl2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(0.70 g, 1.6 mmol), 4-trifluoromethylphenylboronic acid (0.642 g, 3.39mmol), CsF (0.641 g, 4.2 mmol) and Pd (PPh₃)₄ (0.196 g, 0.16 mmol) in 40mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. Thereaction mixture was cooled, and 35 mL of EtOAc and 35 mL of water wereadded. The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yellow oil. The oil was purifiedby chromatography over silica gel (hexane/EtOAc) to give ethyl2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(650 mg) as a colorless liquid.

Step 5

Ethyl2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(640 mg, 1.3 mmol) was dissolved in a mixture of MeCN/H₂O/HCl 15 mL/15mL/1 mL at 0° C. A solution of NaNO₂ (0.138 g, 2.0 mmol) in water (2 mL)was added drop wise at 0° C., and the reaction mixture was stirred for40 min, at the same temperature. A solution of CuCl (1.32 g, 13.4 mmol)in water (5 mL) was added drop wise at 0° C. The reaction mixture washeated to 80° C. for 2 h and the mixture was concentrated under reducedpressure. The reaction mixture was extracted with EtOAc (3×50 mL), andthe combined organic layers were washed with water (50 mL) followed bybrine (50 mL). The solution was dried over Na₂SO₄, filtered andconcentrated to give crude black oil which was purified bychromatography over silica gel (hexane/EtOAc) to give the ethyl2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(380 mg) as a yellow solid.

Step 6

2-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Ethyl2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(320 mg, 0.647 mmol) was dissolved in a MeOH/THF/H₂O (10 mL/10 mL/5 mL)mixture, LiOH (163 mg, 3.88 mmol) was added. The reaction mixture wasstirred at room temperature for 5 h and then concentrated under reducedpressure. Water (10 mL) was added and the reaction mixture was extractedwith EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄,filtered and evaporated under reduced pressure. Purification was achivedby re-crystallization in hexane/ether mixture to give2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid (220 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.74 (d, 2H),7.55 (d, 2H), 7.01 (s, 2H), 4.44 (q, 2H), 3.68 (t, 1H), 1.98 (m, 2H),1.61 (m, 1H), 1.54 (m, 1H), 0.95 (d, 6H)

Example 12772-(5-Chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1

Ethyl 2-(3-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (25 g, 138mmol) in 375 ml of DCM, sulfuryl chloride (9.48 mL 118 mmol) was slowlyadded at 0° C. over a period of 30 min. Diethyl ether (19.6 mL) wasslowly added reaction mixture at 0° C. and stirring was continued for 30min at 0° C. The reaction mixture was slowly warmed to 15° C. for 1 h.After completion of reaction, the mixture was poured onto crushed iceand extracted with DCM (×2). The combined organic layers were washedwith 10% NaHCO₃ solution followed by water. The organic layer was driedover Na₂SO₄, filtered and evaporated under vacuum to give compound ethyl2-(3-chloro-4-hydroxyphenyl)acetate (15 g) as a thick oil.

Step 2

Ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate

To a stirred solution of ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15g, 69 mmol) in CCl₄ (270 mL), bromine (11.1 g, 69 mmol) was added slowly(dissolved in 140 mL of CCl₄) at −10° C. over a period of 30 min. Thereaction mixture was stirred for another 1 h at −10° C. Upon completionof the reaction, the mixture was poured onto crushed ice and extractedwith DCM (×2). The combined organic layers were washed with saturatedNa₂S₂O₃ solution, water, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified byre-crystallization using hexane to yield compound ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (7 g, 7 g starting materialrecovered) as a white solid.

Step 3

Ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (6.5 g, 22 mmol), in DMF(100 mL), K₂CO₃ (7.67 g, 55.6 mmol) was added. Trifluoroethyl iodide(13.16 mL, 133 mmol) was added in a drop wise manner to the reactionmixture at RT. The mixture was then heated at 60° C. for 4 h. Aftercompletion of reaction, the mixture was poured into water and extractedwith ethyl acetate (2×100 mL). The combined organic layers were washedwith water, dried over Na₂SO₄ and concentrated under reduced pressure.The crude compound was purified by column chromatography to givecompound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (6.5 g) as awhite solid.

Step 4

Ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

To a suspension of NaH (0.327 g, 60% in paraffin oil, 8.1 mmol) in DMF(100 mL), slowly added a mixture of ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8mmol) and cyclopropyl methylbromide (0.718 mL, 7.5 mmol) dissolved inDMF (20 mL) at 0° C. for 15 min under an atmosphere of nitrogen. Thereaction mixture was allowed stir at 0° C. for 15 min, upon which themixture was poured onto crushed ice and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with water, brine,dried over Na₂SO₄ and evaporated. The residue was purified by Flashcolumn chromatography to give compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(2.35 g) as a thick syrup.

Step 5

Ethyl2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(500 mg, 1.15 mmol), 4-methyl phenylboronic acid (0.237 g, 1.74 mmol),Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesiumfluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnightat 100° C. After completion of the reaction, the precipitate was removedby filtration. The filtrate was diluted with water and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withwater, brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (375 mg,) as a thick oil.

Step 7

2-(5-Chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoicacid

A mixture of ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (370 mg, 0.84 mmol) and lithiumhydroxide monohydrate (282 mg, 6.7 mmol) in MeOH/THF/Water solventmixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature.After completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water, acidified with 5%HCl solution and extracted with ethyl acetate (2×25 mL). The combinedorganic layers were washed with water, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by FlashColumn Chromatography to give2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoicacid (200 mg) as a white solid. ¹HNMR (CDCl₃): 7.21-7.42 (m, 6H); 3.87(q, 2H); 3.65 (t, 1H); 2.39 (s, 3H), 1.93 (m, 1H); 1.88 (m, 1H); 0.66(m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.1 (m, 1H).

Example 12892-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoicacid

Step 1

Ethyl2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(500 mg, 1.15 mmol), 4-ethyl phenylboronic acid (225 mg, 1.74 mmol),Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesiumfluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnightat 100° C. After completion of the reaction, the precipitate was removedby filtration. The filtrate was diluted with water and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withwater, brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (400 mg) as a thick oil.

Step 2

2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoicacid

A mixture of ethyl2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (222mg, 5.2 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) wasstirred for 3 h at room temperature. After completion of the reaction,the volatiles were removed under reduced pressure. The residue wasdiluted with water, acidified with 5% HCl solution and extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Flash Column Chromatography togive2-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoicacid (200 mg) as a white solid. ¹HNMR (CDCl₃): 7.42 (d, 2H), 7.38 (s,1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 3.66 (t, 1H); 2.73 (q,2H), 1.93 (m, 1H); 1.88 (m, 1H); 1.29 (t, 3H), 0.66 (m, 1H); 0.42 (m,2H); 0.12 (m, 1H); 0.05 (m, 1H).

Example 13132-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1

Ethyl2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(500 mg, 1.15 mmol), 4-thiomethyl phenylboronic acid (293 mg, 1.7 mmol),Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesiumfluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnightat 100° C. After completion of the reaction, the precipitate was removedby filtration. The filtrate was diluted with water and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withwater, brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (360 mg) as a thick oil.

Step 2

2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (350 mg, 0.74 mmol) and lithium hydroxide monohydrate (186mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) wasstirred for 3 h at room temperature. After completion of the reaction,the volatiles were removed under reduced pressure. Residue was dilutedwith water, acidified with 5% HCl solution and extracted with ethylacetate (2×25 mL). The combined organic layers were washed with water,dried with Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Flash Column Chromatography to give2-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (310 mg) as a white solid. ¹HNMR (CDCl₃): 7.46 (d, 2H),7.38 (s, 1H), 7.32 (d, 2H), 7.22 (s, 1H), 3.93 (q, 2H); 3.68 (t, 1H);2.56 (s, 3H), 1.93 (m, 1H); 1.78 (m, 1H); 1.29 (t, 3H), 0.65 (m, 1H);0.42 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).

Example 13252-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1

Ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(500 mg, 1.15 mmol), 4-trifluormethoxy phenylboronic acid (310 mg, 1.65mmol), Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol),Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred forovernight at 100° C. After completion of the reaction, the precipitatewas removed by filtration. The filtrate was diluted with water andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with water, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography to yield ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (260 mg) as a thick oil.

Step 2

2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (260 mg, 0.50 mmol) and lithium hydroxide monohydrate (186mg, 4.44 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml)was stirred for 3 h at room temperature. After completion of thereaction, the volatiles were removed under reduced pressure. The residuewas diluted with water, acidified with 5% HCl solution and extractedwith ethyl acetate (2×25 mL). The combined organic layers were washedwith water, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Flash Column Chromatography togive2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (180 mg) as white solid. ¹HNMR (CDCl₃): 7.56 (d, 2H),7.40 (s, 1H), 7.25 (m, 3H), 3.98 (q, 2H); 3.68 (t, 1H); 2.56 (s, 3H),1.913 (m, 1H); 1.76 (m, 1H); 1.29 (t, 3H), 0.62 (m, 1H); 0.41 (m, 2H);0.12 (m, 1H); 0.05 (m, 1H).

Example 13012-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

Step 1

Ethyl2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate

A mixture of compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(500 mg, 1.15 mmol), 4-isopropyl phenylboronic acid (225 mg, 1.74 mmol),Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesiumfluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnightat 100° C. After completion of the reaction, the precipitate was removedby filtration. The filtrate was diluted with water and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withwater, brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (400 mg) as thick oil.

Step 2

2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid

A mixture of ethyl2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (400 mg, 0.85 mmol) and lithium hydroxide monohydrate (215mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) wasstirred for 3 h at room temperature. After completion of the reaction,the volatiles were removed under reduced pressure. The residue wasdiluted with water, acidified with 5% HCl solution and extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Flash Column Chromatography togive2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (180 mg) as white solid. ¹HNMR (CDCl₃): 7.44 (d, 2H),7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 3.67 (t, 1H);2.98 (m, 1H), 1.93 (m, 1H); 1.78 (m, 1H); 1.28 (d, 6H), 0.66 (m, 1H);0.43 (m, 2H); 0.12 (m, 1H); 0.05 (m, 1H).

Example 12801-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid

Step 1

Ethyl1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a suspension of NaH (0.65 g, 60% in paraffin oil) in DMF (100 mL),slowly added a mixture of ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (3.0 g, 6.8mmol) and 1,3-dibromo propane (1.61 g, 8.0 mmol) dissolved in DMF (20mL) at 0° C. for 15 min under an atmosphere of nitrogen. The reactionmixture was allowed stir at 0° C. for 15 min, upon which the reactionmixture was poured onto crushed ice and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with water, brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byFlash column chromatography to give ethyl1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(2.12 g) as a thick syrup.

Step 2

Ethyl1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of compound ethyl1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(500 mg, 1.2 mmol), 4-methyl phenylboronic acid (0.237 g, 1.68 mmol),Palladium Tetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesiumfluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnightat 100° C. After completion of the reaction, the precipitate was removedby filtration. The filtrate was diluted with water and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withwater, brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate(325 mg) as thick oil.

Step 3

1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid

A mixture of ethyl1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate(300 mg, 0.70 mmol) and lithium hydroxide monohydrate (280 mg, 11.6mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) wasstirred for 3 h at room temperature. After completion of the reaction,the volatiles were removed under reduced pressure. The residue wasdiluted with water, acidified with 5% HCl solution and extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Flash Column Chromatography togive1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid (185 mg, 66%) as white solid. ¹HNMR (CDCl₃): 7.42 (m,2H); 7.32 (s, 1H), 7.23 (d, 2H), 7.18 (s, 1H), 3.87 (q, 2H); 2.85 (m,2H), 2.54 (m, 2H), 2.39 (s, 3H), 2.12 (m, 1H); 1.83 (m, 1H).

Step 4

Ethyl1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of compound ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2mmol), 4-ethyl phenylboronic acid (225 mg, 1.74 mmol), PalladiumTetrakis(triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride(0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C.After completion of the reaction, the precipitate was removed byfiltration. The filtrate was diluted with water and extracted with ethylacetate (2×100 mL). The combined organic layers were washed with water,brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (360 mg) as a thick oil.

Step 5

1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid

A mixture of ethyl1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (350 mg, 0.84 mmol) and lithium hydroxide monohydrate (222mg, 9.2 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml)was stirred for 3 h at room temperature. After completion of thereaction, the volatiles were removed under reduced pressure. The residuewas diluted with water, acidified with 5% HCl solution and extractedwith ethyl acetate (2×25 mL). The combined organic layers were washedwith water, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Flash Column Chromatography togive1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid (260 mg) as white solid. ¹HNMR (CDCl3, 500 MHz): 7.42(d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 2.82 (m,2H), 2.71 (q, 2H), 2.52 (m, 2H), 2.15 (m, 1H), 1.91 (m, 1H); 1.27 (t,3H).

Example 13161-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid

Step 1

Ethyl1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2mmol), 4-thiomethyl phenylboronic acid (293 mg, 1.7 mmol), PalladiumTetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride(0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C.After completion of the reaction, the precipitate was removed byfiltration. The filtrate was diluted with water and extracted with ethylacetate (2×100 mL). The combined organic layers were washed with water,brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (342 mg) as thick oil.

Step 2

1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid

A mixture of ethyl1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (325 mg, 0.70 mmol) and lithium hydroxide monohydrate (186mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) wasstirred for 3 h at room temperature. After completion of the reaction,the volatiles were removed under reduced pressure. The residue wasdiluted with water, acidified with 5% HCl solution and extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Flash Column Chromatography togive1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid (265 mg) as a white solid. ¹HNMR (CDCl₃): 7.46 (d, 2H),7.38 (s, 1H), 7.32 (d, 2H), 7.19 (s, 1H), 3.93 (q, 2H); 2.83 (m, 2H),2.53 (s, 3H), 2.32 (m, 2H), 2.13 (m, 1H), 1.93 (m, 1H).

Example 13041-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid

Step 1

Ethyl1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate

A mixture of ethyl2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (500 mg, 1.2mmol), 4-isopropyl phenylboronic acid (245 mg, 1.68 mmol), PalladiumTetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride(0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C.After completion of the reaction, the precipitate was removed byfiltration. The filtrate was diluted with water and extracted with ethylacetate (2×100 mL). The combined organic layers were washed with water,brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatography toyield ethyl1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (425 mg) as thick oil.

Step 2

1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid

A mixture of ethyl1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (215mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) wasstirred for 3 h at room temperature. After completion of the reaction,the volatiles were removed under reduced pressure. The residue wasdiluted with water, acidified with 5% HCl solution and extracted withethyl acetate (2×25 mL). The combined organic layers were washed withwater, dried with Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Flash Column Chromatography togive1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylic acid (289 mg) as white solid. ¹HNMR (CDCl₃): 7.44 (d, 2H),7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 2.99 (m, 1H),2.86 (m, 2H), 2.52 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H); 1.28 (d, 6H).

Example 18332-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoicacid

Step 1

Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

To a stirred solution of ethyl2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.2g, 4.0 mmol) in dry CCl₄ (60 mL), NCS (0.427 g, 3.2 mmol) was added at0° C. The reaction mixture was allowed to stir for 3 h at roomtemperature to complete the reaction. The reaction mixture was dilutedwith water, extracted with DCM (2×50 mL), the combined organic solventswas dried over Na₂SO₄, filtered and concentrated in vacuo. The crudereaction mixture was purified by column chromatography to yield compoundethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.920 g) as a yellow solid.

Step 2

Ethyl2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate

Ethyl-2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g, 2.6 mmol) was dissolved in a mixture of AcCN/H₂O/HCl(96%) 25 mL/25 mL/1 ml, at 0° C. A solution of NaNO₂ (0.277 g, 4.02mmol) in water (2 mL) was added drop wise at 0° C., and the reactionmixture was stirred for 40 min, at the same temperature. A solution ofKI (4.5 g, 26.8 mmol) in water (10 mL) was added drop wise at 0° C. Thereaction mixture was heated to 70° C. for 1 h. The reaction mixture wasextracted with EtOAc (3×50 mL), and the combined organic layers werewashed with 10% sodium thiosulfate (2×50 mL), water (100 mL) followed bybrine (100 mL). The solution was dried over Na₂SO₄, filtered andconcentrated to give crude black oil which was purified by columnchromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(1.1 g, 90.9%) as yellow oil.

Step 3

Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoate

A mixture of ethyl2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate(1.1 g, 2.4 mmol), 4-trifluoromethylphenylboronic acid (0.928 g, 4.9mmol), CsF (0.926 g, 6.1 mmol) and Pd (PPh₃)₄ (0.283 g, 0.245 mmol) in50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon.The reaction mixture was cooled, and 40 mL of EtOAc and 40 mL of waterwere added. The organic phase was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a yellow oil. The oilwas purified by column chromatography over silica gel (hexane/EtOAc,95:5) to giveethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoate (0.650 g) as a yellow oil.

Step 4

2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoicacid

Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoate (0.65 g, 1.31 mmol) was dissolved in 25 mL of MeOH/THF/H₂O(10:10:5, vvl), LiOH (0.252 g, 10.5 mmol) was added. The reactionmixture was stirred for 5 h at room temperature and concentrated underreduced pressure. Water (10 mL) was added and the reaction mixture wasextracted with EtOAc (3×10 mL). The combined organic phases were driedover Na₂SO₄, filtered and evaporated under reduced pressure.Purification by column chromatography over silica gel (DCM/MeOH, 95:5)gave the2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-3-cyclopropylpropanoicacid (0.585 g) as a white solid. ¹H NMR (500 MHz, CDCl₃/TMS): δ 7.71 (d,2H), 7.39 (d, 2H), 7.22 (s, 1H), 6.91 (s, 1H), 4.23 (q, 2H), 3.72 (t,1H), 1.93 (m, 1H), 1.82 (m, 1H), 0.81 (m, 1H), 0.52 (m, 2H), 0.15 (m,2H).

Example 18361-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid

Step 1

Ethyl1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

To a stirred solution of ethyl1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.0g, 6.3 mmol) in dry CHCl₃ (30 mL), NCS (0.842 g, 6.3 mmol) was added at0° C. The reaction mixture was allowed to stir for 3 at room temperatureto complete the reaction. The reaction mixture was diluted with water,extracted with DCM (2×100 mL), the combined organic solvents was driedover Na₂SO₄, filtered and concentrated in vacuo. The crude reactionmixture was purified by Flash column chromatography to yield ethyl1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(0.4 g) as thick syrup.

Step 2

Ethyl1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate

Ethyl1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(0.45 g, 1.27 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 15mL/10 mL/3.1 mL at 0° C. A solution of NaNO₂ (0.132 g, 1.91 mmol) inwater (1 mL) was added drop wise at 0° C., and the reaction mixture wasstirred for 40 min, at the same temperature. A solution of KI (2.11 g,12.7 mmol) in water (10 mL) was added drop wise at 0° C. The reactionmixture was heated to 80° C. for 1 h. The reaction mixture was extractedwith EtOAc (3×50 mL), and the combined organic layers were washed with10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100mL). The solution was dried over Na₂SO₄, filtered and concentrated togive crude black oil which was purified by column chromatography oversilica gel (hexane/EtOAc, 95:5) to give ethyl1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(0.350 g) as yellow oil.

Step 3

Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate

A mixture of ethyl1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate(0.35, 7.35 mmol), 4-trifluoromethylphenylboronic acid (0.277 g, 1.47mmol), CsF (0.277 g, 1.83 mmol) and Pd (PPh₃)₄ (0.084 g, 0.36 mmol) in20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon.The reaction mixture was cooled, and 20 mL of EtOAc and 20 mL of waterwere added. The organic phase was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure to yellow oil. The oil waspurified by column chromatography over silica gel (hexane/EtOAc, 95:5)to giveethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate(0.182 g) as a colorless oil.

Step 4

1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylicacid

Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate(0.2 g, 0.41 mmol) was dissolved in 25 mL of MeOH/THF/H₂O (10:10:5,vvl), LiOH (0.10 g, 4.1 mmol) was added. The reaction mixture wasstirred for 5 h at room temperature and concentrated under reducedpressure. Water (10 mL) was added and the reaction mixture was extractedwith EtOAc (3×10 mL). The combined organic phases were dried overNa₂SO₄, filtered and evaporated under reduced pressure. Purification bycolumn chromatography over silica gel (DCM/MeOH, 95:5) gave the compound1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylicacid (0.06 g) as a white solid. ¹H NMR (500 MHz, CDCl₃/TMS): δ 7.72 (d,2H), 7.41 (d, 2H), 7.19 (s, 1H), 6.79 (s, 1H), 4.23 (q, 2H), 3.92 (m,2H), 2.58 (m, 2H), 2.19 (m, 1H), 1.97 (m, 1H);

Example 1837Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate

Step 1

Ethyl1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

To a stirred solution of ethyl1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2g, 3.6 mmol) in dry CHCl₃ (60 mL), NCS (0.411 g, 3.08 mmol) was added at0° C. The reaction mixture was allowed to stir for 3 at room temperatureto complete the reaction. The reaction mixture was diluted with water,extracted with DCM (2×100 mL), the combined organic solvents was driedover Na₂SO₄, filtered and concentrated in vacuo. The crude reactionmixture was purified by Flash column chromatography to yield ethyl1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate(0.860 g) as a thick syrup.

Step 2

Ethyl1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate

Ethyl1-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate(0.86 g, 2.3 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 10mL/8 mL/2.1 mL at 0° C. A solution of NaNO₂ (0.243 g, 3.5 mmol) in water(1 mL) was added drop wise at 0° C., and the reaction mixture wasstirred for 40 min, at the same temperature. A solution of KI (3.9 g,23.5 mmol) in water (10 mL) was added drop wise at 0° C. The reactionmixture was heated to 80° C. for 1 h. The reaction mixture was extractedwith EtOAc (3×50 mL), and the combined organic layers were washed with10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100mL). The solution was dried over Na₂SO₄, filtered and concentrated togive crude black oil which was purified by column chromatography oversilica gel (hexane/EtOAc, 95:5) to give ethyl1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate(0.580 g) as pale yellow oil.

Step 3

Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate

A mixture of ethyl1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate(0.58, 1.2 mmol), 4-trifluoromethylphenylboronic acid (0.56 g, 2.4mmol), CsF (0.46 g, 3.0 mmol) and Pd (PPh₃)₄ (0.14 g, 0.12 mmol) in 20mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. Thereaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water wereadded. The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yellow oil. The oil was purifiedby column chromatography over silica gel (hexane/EtOAc, 95:5) to giveethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate(0.480 g) as a color less oil.

Step 4

1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylicacid

Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate (0.32 g, 0.64 mmol) was dissolved in 25 mL of MeOH/THF/H₂O(10:10:5, vvl), LiOH (0.163 g, 3.88 mmol) was added. The reactionmixture was stirred for 5 h at room temperature and concentrated underreduced pressure. Water (10 mL) was added and the reaction mixture wasextracted with EtOAc (3×10 mL). The combined organic phases were driedover Na₂SO₄, filtered and evaporated under reduced pressure.Purification by column chromatography over silica gel (DCM/MeOH, 95:5)gave the1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylicacid (0.220 g, 73%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.69(d, 2H), 7.41 (d, 2H), 7.26 (s, 1H), 6.92 (s, 1H), 4.22 (q, 2H), 3.71(m, 2H), 1.98 (m, 2H), 1.81 (m, 4H).

Example 18322-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoicacid

Step 1

Ethyl2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.25 g,0.75 mmol) in dry CHCl₃ (20 mL), NCS (0.08 g, 0.6 mmol) was added at 0°C. The reaction mixture was allowed to stir for 3 at room temperature tocomplete the reaction. The reaction mixture was diluted with water,extracted with DCM (2×100 mL), the combined organic solvents was driedover Na₂SO₄, filtered and concentrated in vacuo. The crude reactionmixture was purified by Flash column chromatography to yield ethyl2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(0.15 g) as thick syrup.

Step 2

Ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate

Ethyl2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(0.7 g, 1.9 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 20mL/20 mL/1.3 mL at 0° C. A solution of NaNO₂ (0.197 g, 2.8 mmol) inwater (2 mL) was added drop wise at 0° C., and the reaction mixture wasstirred for 40 min, at the same temperature. A solution of KI (3.16 g,19.0 mmol) in water (10 mL) was added drop wise at 0° C. The reactionmixture was heated to 80° C. for 1 h. The reaction mixture was extractedwith EtOAc (3×100 mL), and the combined organic layers were washed with10% sodium thiosulfate (2×50 mL), water (100 mL) followed by brine (100mL). The solution was dried over Na₂SO₄, filtered and concentrated togive crude black oil which was purified by column chromatography oversilica gel (hexane/EtOAc, 95:5) to giveethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(0.35 g) as pale yellow oil.

Step 3

Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate

A mixture ofethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate(0.5, 1.04 mmol), 4-trifluoromethylphenylboronic acid (0.96 g, 2.09mmol), CsF (0.395 g, 2.6 mmol) and Pd (PPh₃)₄ (0.121 g, 0.104 mmol) in50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon.The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of waterwere added. The organic phase was separated, dried over Na₂SO₄, filteredand concentrated under reduced pressure to yellow oil. The oil waspurified by column chromatography over silica gel (hexane/EtOAc, 95:5)to giveethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate(0.265 g,) as a colorless oil.

Step 4

2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoicacid

Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate(0.35 g, 0.733 mmol) was dissolved in 25 mL of MeOH/THF/H₂O (10:10:5,vvl), LiOH (0.176 g, 7.33 mmol) was added. The reaction mixture wasstirred for 5 h at room temperature and concentrated under reducedpressure. Water (10 mL) was added and the reaction mixture was extractedwith EtOAc (3×10 mL). The combined organic phases were dried overNa₂SO₄, filtered and evaporated under reduced pressure. Purification bycolumn chromatography over silica gel (DCM/MeOH, 95:5) gave the compound2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoicacid (0.085 g) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.69 (d,2H), 7.41 (d, 2H), 7.20 (s, 1H), 6.86 (s, 1H), 4.23 (q, 2H), 3.71 (t,1H), 2.01 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H).

Example 19081-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid

2-(Cyclopropylmethoxy)-4-fluoro-1-nitrobenzene

Cyclopropylmethanol (15 g, 207 mmol) was added to a stirred suspensionof NaH (60% in mineral oil, 8.37 g) in 200 mL THF over 15 min at 0° C.under nitrogen. The reaction mixture was allowed to warm to roomtemperature and stirred for 1 h. A solution of2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was addeddrop wise at 0° C. The reaction mixture was stirred at 0° C. for 2 h andthen poured into ice water. The reaction mixture was extracted withethyl acetate (3×100 mL). The combined organic layers were dried overMgSO₄ and concentrated under reduced pressure to give 22.0 g of productas orange oil (86%).

Step 2

Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl) malonate

Diethyl malonate (9.8 g, 1.1 eq.) was added to a stirred suspension ofsodium hydride (60% in mineral oil, 2.09 g) in 88 mL DMF over 15 min. at0° C. under nitrogen. The reaction mixture was allowed to warm to roomtemperature and stirred for 1 h. A solution of2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq.) in DMF (88mL) was added drop wise at 0° C., and the reaction mixture was heated to100° C. for 3 h. The reaction mixture was allowed to cool to roomtemperature, poured into ice water and extracted with EtOAc (3×100 mL).The combined organic phases were washed with water (3×100 mL), brine(100 mL) and dried (MgSO₄). Evaporation of solvent under reducedpressure gave 10.0 g of crude product which was purified by silica gelchromatography (hexane/EtOAc) gave 7.0 g of the desired product (42%)

¹H-NMR (CDCl₃, 200 MHz): 0.4 (m, 2H), 0.71 (m, 2H), 1.3 (m, 1H), 1.3 (t,6H), 3.96 (d, 2H), 4.25 (q, 4H), 4.5 (s, 1H), 7.02 (d, 1H), 7.18 (s,1H), 7.81 (d, 2H).

Step 3

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate

i) Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl) malonate (10 g) wasdissolved in 100 mL ethanol and cooled to 0° C., NaOH solution (4 eq)was added slowly to the reaction mixture for about 15 min. The reactionmixture was heated gently up to 60° C. for 5 h. Progress of the reactionwas monitored by TLC analysis. After complete conversion of startingmaterial solvent was evaporated under reduced pressure, the residuedissolved in H₂O, acidified with 6N HCl to pH-2. The solid material wascollected via filtration, washed with water, dried under reducedpressure to yield 6.5 g (90%) of2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid as a yellow solid.

¹H-NMR (CDCl₃, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.28 (m, 1H), 3.71(s, 2H), 4.01 (d, 2H), 7.02 (d, 1H), 7.23 (s, 1H), 7.81 (d, 1H).

ii) 2-(3-(Cyclopropylmethoxy)-4-nitrophenyl)acetic acid (6.5 g) wastaken up in an ethanolic HCl solution (50 mL, 25%) and refluxed for 4 h,monitored by TLC. The reaction mixture was concentrated in vacuo todryness and dissolved in ethyl acetate. The mixture was washed withNaHCO₃ solution, dried over NaSO₄ and concentrated in vacuo to givecrude yellow solid which was purified by recrystallization to give thedesired product (4.2 g).

¹H-NMR (CDCl3, 200 MHz): 0.36 (m, 2H), 0.58 (m, 2H), 1.12 (t, 3H), 1.28(m, 1H), 3.71 (s, 2H), 4.01 (d, 2H), 4.21 (q, 2H), 7.02 (d, 1H), 7.23(s, 1H), 7.81 (d, 1H).

Step 4

Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100mL) was added Pd(OH)₂ (2 g). The mixture was hydrogenated under a H₂atmosphere for 6 h at room temperature. The reaction mixture wasfiltered through a pad of Celite™, washing with MeOH. The combinedfiltrates were concentrated under reduced pressure to yield 7.5 g of thedesired product as an oil.

¹H-NMR (CDCl3, 200 MHz): 0.38 (m, 2H), 0.61 (m, 2H), 1.23 (m, 1H), 1.23(t, 3H), 3.51 (s, 2H), 3.80 (d, 2H), 4.16 (q, 2H), 6.72 (m, 3H).

Step 5

Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dryCCl₄ (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reactionmixture was allowed to stir for 3 h at room temperature to complete thereaction. The reaction mixture was diluted with water, extracted withDCM (2×50 mL), the combined organic solvents was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude reaction mixture waspurified by column chromatography to yield Ethyl2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as ayellow solid.

Step 6

Ethyl 2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate

Ethyl-2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)-acetate (2.5 g,10.0 mmol) was dissolved in a mixture of AcCN/H₂O/HCl (96%) 50 mL/50mL/25 mL at 0° C. A solution of NaNO₂ (3.2 g, 1.16 eq) in water (40 mL)was added drop wise at 0° C., and the reaction mixture was stirred for40 min, at the same temperature. A solution of KI (30 g, 30.1 mmol) inwater (80 mL) was added drop wise at 0° C. The reaction mixture washeated to 50° C. for 2.5 h and the solvent was evaporated. The reactionmixture was extracted with EtOAc (3×50 mL), and the combined organiclayers were washed with 10% sodium thiosulfate (2×50 mL), water (300 mL)followed by brine (300 mL). The solution was dried over Na₂SO₄, filteredand concentrated in vacuo to give crude black oil which was purified bychromatography over silica gel (hexane/EtOAc) to give the ethyl2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (1.2 g)

Step 7

Ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate

A mixture of compound ethyl2-(3-chloro-5-(cyclopropylmethoxy)-4-iodophenyl)acetate (5.1 g, 12.9mmol), 4-trifluoromethylphenylboronic acid (3.66 g, 19 mmol), CsF (3.9g, 25.8 mmol) and Pd (PPh₃)₄ (1.5 g, 1.3 mmol) in 100 mL anhydrous1,2-dimethoxy ethane was refluxed for 8 h under argon. The reactionmixture was cooled, and 75 mL of EtOAc and 75 mL of water were added.The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yellow oil. The oil was purifiedby column chromatography over silica gel (hexane/EtOAc) to give ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate(3.2 g) as yellow oil.

Step 8

1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid

Ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate(0.5 g, 1.2 mmol) was dissolved in 10 mL anhydrous DMF, NaH (60% wt. inoil, 0.058 g, 2.4 mmol) was added at 0° C. The reaction mixture wasstirred for 0.5 h at 25° C. and 1,3-dibromopropane (1.5 mL) was addeddrop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h andsaturated NH₄Cl solution (10 mL) was added. The reaction mixture wasextracted with EtOAc (3×20 mL) and the combined organic phases werewashed with water (3×20 mL) and brine (20 mL), and dried over MgSO₄,filtered and concentrated under reduced pressure to give a (320 mg) ofcolorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, vvl) and0.163 g LiOH added. The reaction mixture was refluxed for 5 h andconcentrated under reduced pressure. Water (10 mL) was added and thereaction mixture was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried over MgSO₄, filtered and concentrated underreduced pressure. Purification by column chromatography over silica gel(hexane/EtOAc 9:1) gave1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid (0.210 g) as a white solid. ¹HNMR (300 MHz, CDCl₃): δ7.68 (d, 2H), 7.41 (d, 2H), 7.06 (s, 1H), 6.78 (s, 1H), 3.78 (d, 2H),2.86 (m, 2H), 2.58 (m, 2H), 2.16 (m, 1H), 1.95 (m, 1H), 1.03 (m, 1H),0.46 (m, 2H), 0.18 (m, 2H).

Example 19091-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid

1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid

Ethyl2-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)acetate(0.5 g,) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil,0.058 g, 2.4 mmol) was added at 0° C. The reaction mixture was stirredfor 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g) was added drop wiseat 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturatedNH₄Cl solution (10 mL) was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the combined organic phases were washed withwater (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered andconcentrated under reduced pressure to give a (320 mg, 0.64 mmol) ofcolorless oil. The oil was dissolved in 10 mL of EtOH/H₂O (9:1, vvl) andLiOH (0.163 g, 3.88 mmol) added. The reaction mixture was refluxed for 5h and concentrated under reduced pressure. Water (10 mL) was added andthe reaction mixture was extracted with EtOAc (3×10 mL). The combinedorganic phases were dried over MgSO₄, filtered and concentrated underreduced pressure. Purification by column chromatography over silica gel(hexane/EtOAc 9:1) to give1-(2-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (220 mg) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ7.68 (d, 2H), 7.41 (d, 2H), 7.16 (s, 1H), 6.91 (s, 1H), 3.78 (d, 2H),2.66 (m, 2H), 1.97 (m, 2H), 1.79 (m, 4H), 1.03 (m, 1H), 0.46 (d, 2H),0.18 (d, 2H);

Example 24182-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate

Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (2.2 g, 7.8 mmol)was dissolved in 20 mL anhydrous DMF and NaH (60% wt. in oil, 0.189 g,7.8 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 hat 25° C. and isobutyl bromide (1.08 g, 7.8 mmol) was added drop wise at0° C. The reaction mixture was stirred at 0° C. for 1 h and saturatedNH₄Cl solution (10 mL) was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the combined organic phases were washed withwater (3×20 mL) and brine (20 mL), and dried over MgSO₄, filtered andconcentrated under reduced pressure to give ethyl2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.06 g) ofcolorless oil.

Step 2

Ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.0 g, 5.9mmol), in dry MeOH (50 mL) Pd(OH)₂ (1.1 g) was added. The mixture wasreduced under an atmosphere of H₂ for 6 h at room temperature. Thereaction mixture was filtered off through a pad of Celite™, washing withMeOH. The combined filtrates were concentrated under reduced pressure toyield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(1.69 g) as a thick liquid.

Step 3

Ethyl2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.65 g, 5.4mmol) in dry CCl₄ (60 mL), NBS (0.96 g, 5.4 mmol) was added at 0° C. Thereaction mixture was allowed to stir for 3 at room temperature tocomplete the reaction. The reaction mixture was diluted with water,extracted with DCM (2×50 mL), the combined organic solvents was driedover Na₂SO₄, filtered and concentrated in vacuo. The crude reactionmixture was purified by column chromatography to yield ethyl2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5g) as a yellow solid.

Step 4

Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

A mixture of ethyl2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5g, 3.9 mmol), 4-trifluoromethylphenylboronic acid (1.1 g, 5.8 mmol), CsF(1.47 g, 7.8 mmol) and Pd (PPh₃)₄ (0.45 g, 0.39 mmol) in 75 mL anhydrous1,2-dimethoxy ethane was refluxed for 8 h under argon. The reactionmixture was cooled, and 75 mL of EtOAc and 75 mL of water were added.The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yellow oil. The oil was purifiedby chromatography over silica gel (hexane/EtOAc) to giveethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (1.2 g) as a yellow oil.

Step 5

Ethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

Ethyl-2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.2 g, 0.44 mmol) was dissolved in a mixture of AcCN/H₂O/HCl10 mL/10 mL/1 mL at 0° C. A solution of NaNO₂ (0.039 g, 0.53 mmol) inwater (1 mL) was added drop wise at 0° C., and the reaction mixture wasstirred for 40 min, at the same temperature. A solution of CuCl (0.22 g,2.2 mmol) in water (5 mL) was added drop wise at 0° C. The reactionmixture was heated to 40° C. for 2.0 h and the solvent was evaporated.The reaction mixture was extracted with EtOAc (3×50 mL), and thecombined organic layers were washed with water (30 mL) followed by brine(20 mL). The solution was dried over Na₂SO₄, filtered and concentratedin vacuo to give crude black oil which was purified by chromatographyover silica gel (hexane/EtOAc) to giveethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(0.12 g) as a thick oil.

Step 6

2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Theethyl-2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(120 mg, 0.255 mmol) dissolved in 10 mL of MeOH/THF/H₂O (10 mL/10 mL/5mL) and LiOH (30 mg, 1.2 mmol) was added. The reaction mixture wasstirred at room temperature for 5 h and concentrated under reducedpressure. Water (10 mL) was added and the reaction mixture was extractedwith EtOAc (3×10 mL). The combined organic phases were dried over MgSO₄,filtered and evaporated under reduced pressure. Purification by columnchromatography over silica gel (DCM:MeOH 9:1) gave2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid (89 mg) as a white solid. ¹H-NMR (500 MHz, CDCl₃): 7.68 (d, 2H),7.55 (d, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 3.96 (d, 2H), 3.64 (t, 1H),1.98 (m, 1H), 1.68 (m, 1H), 1.55 (m, 1H), 1.32 (m, 1H), 0.91 (d, 6H),0.64 (m, 2H), 0.42 (m, 2H);

Example 32052-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoicacid

Step 1

Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12 g, 40.816 mmol) in DMSO(80 mL) were added K₂CO₃ (14.08 g, 102.020 mmol) andcyclopropylmethylbromide (5 mL, 4.880 mmol) at RT under inertatmosphere. The reaction mixture was stirred at 80° C. temperature overa period of 14 h. After completion of starting material (by TLC), thereaction mixture was cooled to RT and quenched with water and extractedwith EtOAc (3×100 mL). Combined organic layers were washed with water(3×75 mL), brine and dried over Na₂SO₄. After filtration andconcentration under reduced pressure, the crude material was purified bycolumn chromatography to afford ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (10 g) yellowsolid.

Step 2

Ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate

To a stirred solution of NaH (0.3 g, 12.5 mmol) in DMF (10 mL) was addedethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (2.0 g,5.70 mmol) at 0° C. The reaction mixture was stirred at 0° C. over aperiod of 30 min. To the reaction mixture was added 2-bromo ethyl methylether (0.87 g, 6.25 mmol) and stirred at 0 oC for 30 min. Aftercompletion of starting material (by TLC), the reaction mixture wasdiluted with water (20 mL), acidified with 1N HCl (pH=5) and extractedwith EtOAc (3×50 mL). Combined organic layers were washed with water(3×25 mL), brine and dried over anhydrous Na₂SO₄. After filtration andconcentration under reduced pressure, the crude material was purified bycolumn chromatography to afford ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate(560 mg) as an off white solid.

Step 3

Ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate(2.3 g, 5.660 mmol) in a mixture of DMF (50 mL) and water (5 mL) wereadded Cs₂CO₃ (6.4 g, 19.815 mmol), Pd(TPP)₄ (1.3 g, 1.120 mmol) and4-(trifluoromethyl)phenyl boronic acid (1.29 g, 6.780 mmol) at RT underN₂ atmosphere and the resulting mixture was stirred at 80° C. for 14 h.After completion of starting material (by TLC), filtered off thecatalyst and celite bed was washed with EtOAc and extracted with EtOAc(3×100 mL). Combined organic layers were washed with water (3×50 mL),brine and dried over anhydrous Na₂SO₄. After filtration andconcentration under reduced pressure, the crude material was purified bycolumn chromatography to afford ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate(1.2 g) as an off white solid.

Step 4

2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoicacid

To a stirred solution of ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoate(0.3 g, 0.638 mmol) in a mixture of THF (10 mL), methanol (10 mL) andwater (5 mL) was added LiOH.H₂O (53 mg, 12.030 mmol) at room temperatureand the mixture was stirred at RT for 2 h. After complete consumption ofstarting material as monitored by TLC, the reaction mixture was dilutedwith water (10 mL) and acidified using 1 N HCl at 0° C. The aqueouslayer was extracted with EtOAc (2×20 mL); combined organic extracts werewashed with water (20 mL), brine (30 mL), dried over anhydrous Na₂SO₄and concentrated in vacuo. The crude material was purified by columnchromatography to afford2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methoxybutanoicacid (100 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ ppm 7.68(m, 4H), 7.40 (s, 1H), 7.20 (s, 1H), 3.80 (t, 1H), 3.41 (d, 2H), 3.25(m, 5H), 2.39 (m, 1H), 1.99 (m, 1H), 0.95 (m, 1H), 0.4 (d, 2H), 0.0 (m,2H).

Example 32062-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid

Step 1

Ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methylpentanoate

To a stirred solution of NaH (0.76 g, 15.82 mmol) in DMF (50 mL) wasadded compound 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoicacid (5.0 g, 14.4 mmol) at 0° C. The reaction mixture was stirred at 0°C. over a period of 30 min. To the reaction mixture was added isobutylbromide (2.93 g, 21.57 mmol) and stirred at 0° C. for 1 h. Aftercompletion of starting material (by TLC), diluted with water (40 mL),acidified with 1N HCl (pH=5) and extracted with EtOAc (3×100 mL).Combined organic layers were washed with water (3×50 mL), brine anddried over anhydrous Na₂SO₄. After filtration and concentration underreduced pressure, the crude material was purified by columnchromatography to afford ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate(5.0 g) as a liquid.

Step 2

Ethyl2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methyl pentanoate(0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and water (5 mL) wereadded Cs₂CO₃ (1.4 g, 4.325 mmol), Pd (TPP)₄ (286 mg, 2.475 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (355 mg,1.363 mmol) at RT under N₂ atmosphere and the resulting mixture wasstirred at 80° C. for 14 h. After completion of starting material (byTLC), the solids were removed via filtration through a bed of Celite™was washing with EtOAc (3×100 mL). The combined organic layers werewashed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by column chromatography to afford ethyl2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(100 mg) as an off white solid.

Step 3

2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid

To a stirred solution of ethyl2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(0.1 g, 0.218 mmol) in a mixture of THF (10 mL), methanol (10 mL) andwater (5 mL) was added LiOH.H₂O (45 mg, 1.090 mmol) at room temperatureand the mixture was stirred at RT for 2 h. After complete consumption ofstarting material as monitored by TLC, the reaction mixture was dilutedwith water (10 mL) and acidified using 1 N HCl at 0° C. The aqueouslayer was extracted with EtOAc (2×20 mL); combined organic extracts werewashed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude material was purified bycolumn chromatography to afford2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid (39 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm)9.05 (s, 1H), 8.2 (m, 2H), 7.73 (m, 1H), 7.40 (s, 1H), 7.30 (s, 1H),3.63 (t, 1H), 3.40 (d, 2H), 1.99 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H),0.93 (m, 7H), 0.38 (d, 2H), −0.5 (d, 2H).

Example 5142-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid

Step 1

Ethyl2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(0.5 g, 1.240 mmol) in a mixture of DMF (20 mL) and water (5 mL) wereadded Cs₂CO₃ (1.4 g, 4.342 mmol), Pd(TPP)₄ (286 mg, 2.480 mmol) and5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole(355 mg, 1.364 mmol) at RT under N₂ atmosphere and the resulting mixturewas stirred at 80° C. for 14 h. After completion of starting material(by TLC), the solids were removed via filtration through a bed ofCelite™ was washing with EtOAc (3×100 mL). The combined organic layerswere washed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by column chromatography to afford ethyl2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(250 mg) as an off white solid.

2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid

To a stirred solution of ethyl2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(0.25 g, 0.565 mmol) in a mixture of THF (10 mL), methanol (10 mL) andwater (5 mL) was added LiOH.H₂O (118.7 mg, 2.828 mmol) at roomtemperature and the mixture was stirred at RT for 2 h. After completeconsumption of starting material as monitored by TLC, the reactionmixture was diluted with water (10 mL) and acidified using 1 N HCl at 0°C. The aqueous layer was extracted with EtOAc (2×20 mL); combinedorganic extracts were washed with water (10 mL), brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was purified by column chromatography to afford compound2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid (152 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm)7.92 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H),3.65 (t, 1H), 3.48 (d, 2H), 1.95 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H),1.22 (m, 1H0, 0.93 (d, 6H), 0.39 (d, 2H), 0.0 (m, 2H).

Example 5242-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid

Step 1

Ethyl2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(0.5 g, 1.239 mmol) in a mixture of DMF (10 mL) and water (5 mL) wereadded Cs₂CO₃ (1.4 g, 4.325 mmol), Pd(TPP)₄ (286 mg, 2.475 mmol) and5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiazdiazole (355mg, 1.363 mmol) at RT under N₂ atmosphere and the resulting mixture wasstirred at 80° C. for 14 h. After completion of starting material (byTLC), the solids were removed via filtration through a bed of Celite™was washing with EtOAc (3×100 mL). The combined organic layers werewashed with water (3×50 mL), brine and dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by column chromatography to afford ethyl2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(222 mg) as an off white solid.

Step 2

2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoicacid

To a stirred solution of ethyl2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate(0.22 g, 0.479 mmol) in a mixture of THF (5 mL), methanol (5 mL) andwater (2 mL) was added LiOH.H₂O (60.3 mg, 1.438 mmol) at roomtemperature and the mixture was stirred at RT for 2 h. After completeconsumption of starting material as monitored by TLC, the reactionmixture was diluted with water (10 mL) and acidified using 1 N HCl at 0°C. The aqueous layer was extracted with EtOAc (2×20 mL); combinedorganic extracts were washed with water (10 mL), brine (20 mL), driedover anhydrous Na₂SO₄ and concentrated in vacuo. The crude material waspurified by column chromatography to afford2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (105 mg, 50.0%) as an off white solid. ¹HNMR (500 MHz)(CDCl₃): δ (ppm) 8.18 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.42 (s, 1H),7.18 (s, 1H), 3.68 (t, 1H), 3.43 (d, 2H), 2.00 (m, 1H), 1.70 (m, 1H),1.58 (m, 1H), 0.98 (d, 6H), 0.88 (m, 1H), 0.38 (d, 2H), 0.0 (m, 2H).

Example 32072-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl 2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate

To a stirred compound ethyl2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (1.0 g, 3.174 mmol) inDCM (15 ml) chlorosulfonic acid (2 mL, 28.571 mmol) was added. Thereaction mixture was stirred for 14 h at 80° C. under N₂ atmosphere.After completion of starting material (by TLC), the reaction mixture wasquenched with NaHCO₃ solution and extracted with DCM (3×100 mL).Combined organic layers were washed with water (3×75 mL), brine anddried over Na₂SO₄, filtered and concentrated in vacuo to give ethyl2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate (0.5g) as a liquid.

Step 2

Ethyl2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(3-bromo-5-(chlorosulfonyl)-4-hydroxyphenyl)-4-methyl pentanoate (0.73g, 1.765 mmol) in THF (20 mL) was added N,N-dimethylamine solution (5.2mL, 10.592 mmol) at RT under inert atmosphere. The reaction mixture wasstirred at RT over a period of 14 h. After completion of startingmaterial (by TLC), the reaction mixture was quenched with water andextracted with EtOAc (3×100 mL). The combined organic layers were washedwith water (3×75 mL), brine and dried over Na₂SO₄. After filtration andconcentration under reduced pressure, the crude material was purified bycolumn chromatography to afford ethyl2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate(0.6 g) as a pale yellow liquid.

Step 3

Ethyl2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate

To a stirred solution of ethyl2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate(0.75 g, 1.77 mmol) in DMSO (25 mL) were added K₂CO₃ (367 mg, 2.106mmol) and cyclopropylmethylbromide (0.2 mL, 2.13 mmol) at RT under inertatmosphere. The reaction mixture was stirred at 80° C. temperature overa period of 14 h. After completion of starting material (by TLC), thereaction mixture was cooled to RT and quenched with water and extractedwith EtOAc (3×100 mL). Combined organic layers were washed with water(3×75 mL), brine and dried over Na₂SO₄. After filtration andevaporation, the crude material was purified by column chromatography toafford ethyl2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate(350 mg) as a liquid.

Step 4

2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

To a stirred solution of2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate(0.5 g, 1.049 mmol) in a mixture of DMF (10 mL) and water (5 mL) wereadded Cs₂CO₃ (1.19 g, 3.670 mmol), Pd(TPP)₄ (243 mg, 0.209 mmol) and4-(trifluoromethyl)phenylbornate (220 mg, 1.150 mmol) at RT under N₂atmosphere and the resulting mixture was stirred at 80° C. for 14 h.After completion of starting material (by TLC), filtered off thecatalyst and celite bed was washed with EtOAc and extracted with EtOAc(3×100 mL). The combined organic layers were washed with water (3×50mL), brine and dried over anhydrous Na₂SO₄. After filtration andconcentration in vacuo, the crude material was purified by columnchromatography to afford2-(6-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid (100 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm)7.83 (s, 1H), 7.72 (m, 4H), 7.51 (s, 1H), 3.73 (m, 1H), 3.38 (d, 2H),2.95 (s, 3H), 2.87 (s, 3H), 2.01 (m, 1H), 1.65 (m, 1H), 1.51 (m, 1H),0.91 (m, 7H), 0.40 (d, 2H), 0.00 (m, 2H).

Step 5

Ethyl2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a stirred solution of ethyl2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(1.0 g, 2.227 mmol) in a mixture of HCl:H2O (0.81 mL, 6.681 mmol) wasadded NaNO₂ (0.180 g, 2.672 mmol). After being stirred for 1 h at 0° C.then added KI (3.69 g, 22.271 mmol) at 0° C. under inert atmosphere. Thereaction mixture was stirred at 100° C. temperature over a period of 2h. After completion of starting material (by TLC), the reaction mixturewas cooled to RT and extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with water (3×75 mL), brine and dried overNa₂SO₄. After filtration and concentration in vacuo, the crude materialwas purified by column chromatography to afford ethyl2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(0.93 g) as a solid.

Example 32102-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a stirred solution of ethyl2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.25 g, 0.447 mmol) in NMP (10 mL)was added CuCN (50 mg, 0.536 mmol) at RT under inert atmosphere. Thereaction mixture was stirred at 200° C. temperature over a period of 2h. After completion of starting material (by TLC), the reaction mixturewas cooled to RT and extracted with EtOAc (3×20 mL). Combined organiclayers were washed with water (3×15 mL), brine and dried over Na₂SO₄.After filtration and evaporation, the crude material was purified bycolumn chromatography to afford ethyl2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.125 g) a solid.

Step 2

2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

To a stirred solution of ethyl2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.125 g, 0.272 mmol) in a mixture ofTHF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H₂O (34 mg,0.816 mmol) at room temperature and the mixture was stirred at RT for 2h. After complete consumption of starting material as monitored by TLC,the reaction mixture was diluted with water (10 mL) and acidified using1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL);combined organic extracts were washed with water (10 mL), brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude material was purified by column chromatography to afford2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid (50 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm)7.70 (m, 4H), 7.61 (s, 1H), 7.51 (s, 1H), 3.71 (t, 1H), 3.55 (m, 2H),2.00 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 1.02 (m, 1H), 0.91 (d, 6H),0.45 (m, 2H), 0.05 (m, 2H).

Example 32082-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

Step 1

Ethyl2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate

To a stirred solution of ethyl2-(5-amino-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(1.0 g, 2.604 mmol) in a mixture of HCl:H₂O (0.86 mL, 10.4 mmol) and THF(10 mL) was added NaNO₂ (0.215 g, 3.92 mmol). After being stirred for 1h at 0° C. then added NaSMe (368 mg, 0.260 mmol) at 0° C. under an inertatmosphere. The reaction mixture was stirred at RT over a period of 14h. After complete consumption of starting material (by TLC), thereaction mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with water (3×75 mL), brine and dried overNa₂SO₄. After filtration and concentration under vacuo, the crudematerial was purified by column chromatography to afford ethyl2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(0.93 g) as a solid.

Step 2

2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid

To a stirred solution of ethyl2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate(80 mg, 0.166 mmol) in a mixture of THF (10 mL), methanol (10 mL) andwater (5 mL) was added LiOH.H₂O (20 mg, 0.832 mmol) at room temperatureand the mixture was stirred at RT for 2 h. After complete consumption ofstarting material as monitored by TLC, the reaction mixture was dilutedwith water (10 mL) and acidified using 1 N HCl at 0° C. The aqueouslayer was extracted with EtOAc (2×20 mL); combined organic extracts werewashed with water (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under vacuo. The crude material was purifiedby column chromatography to afford2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoicacid (38 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm)7.75 (d, 2H), 7.65 (d, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 3.65 (t, 1H),3.60 (d, 2H), 2.82 (s, 3H), 1.98 (m, 1H), 1.65 (m, 1H), 1.5 (m, 1H),1.22 (m, 1H), 0.9 (d, 6H), 0.38 (d, 2H), 0.01 (d, 2H).

Example 32092-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoicacid

Step 1

Ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate

To a stirred solution of NaH (40 mg, 0.830 mmol) in DMF (5 mL) was addedcompound ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(300 mg, 0.728 mmol) and stirred at 0° C. for 1 h. To the reactionmixture at 0° C. was added isopropyl bromide (0.08 mL, 0.880 mmol) andcontinued stirring at 0° C. over a period of 30 min. After completeconsumption of the starting material (by TLC), the reaction mixture wasdiluted with water (20 mL), acidified with 1N Hcl (pH=5) and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with water(3×15 mL), brine and dried over anhydrous Na₂SO₄. After filtration andconcentration under educed pressure, the crude material was purified bycolumn chromatography to afford ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate (120mg) as a liquid.

Step 2

2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoicacid

To a stirred solution of ethyl2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-3-methylbutanoate(0.12 g, 0.260 mmol) in a mixture of THF (5 mL), methanol (5 mL) andwater (2 mL) was added LiOH.H₂O (75 mg, 1.320 mmol) at room temperatureand the mixture was stirred at RT for 2 h. After complete consumption ofthe starting material, as monitored by TLC, the reaction mixture wasdiluted with water (10 mL) and acidified using 1 N HCl at 0° C. Theaqueous layer was extracted with EtOAc (2×20 mL); combined organicextracts were washed with water (10 mL), brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo. The crude material waspurified by column chromatography to affordethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylbutanoate(100 mg) as an off white solid. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.66(m, 4H), 7.41 (s, 1H), 7.20 (s, 1H), 3.41 (d, 2H), 3.15 (d, 1H), 2.3 (m,1H), 1.12 (d, 3H), 0.97 (m, 1H), 0.72 (d, 3H), 0.40 (d, 2H), 0.00 (d,2H).

Example 4822-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoicacid

Step 1

Ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate

To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15 mL) was addedethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate(500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL, 0.15mmol) at 0° C. The reaction mixture was stirred at 0° C. over a periodof 30 min. After completion of starting material (by TLC), diluted withwater (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc(3×30 mL). Combined organic layers were washed with water (3×15 mL),brine and dried over anhydrous Na₂SO₄. After filtration and evaporation,the crude material was purified by column chromatography to afford ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate(300 mg) as liquid.

Step 2

2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoicacid

To a stirred solution of ethyl2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (0.1 g, 0.404 mmol) in a mixtureof THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H₂O (85mg, 2.024 mmol) at room temperature and the mixture was stirred at RTfor 2 h. After complete consumption of the starting material asmonitored by TLC, the reaction mixture was diluted with water (10 mL)and acidified using 1 N HCl at 0° C. The aqueous layer was extractedwith EtOAc (2×20 mL) the combined organic extracts were washed withwater (10 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and evaporatedunder vacuum. The crude material was purified by column chromatographyto2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoicacid (38 mg) as sticky syrup. ¹HNMR (500 MHz) (CDCl₃): δ (ppm) 7.71 (m,4H), 7.39 (s, 1H), 7.19 (s, 1H), 3.92 (m, 1H), 3.41 (d, 2H), 3.08 (m,1H), 2.54 (m, 1H), 0.96 (m, 1H), 0.40 (d, 2H), 0.00 (m, 2H).

The following examples can also be made using analogous procedures asdescribed previously, substituting the appropriate reagents known tothose of ordinary skill in the art.

Example 3211

-   2-(5-chloro-6-(cyclopropylmethoxy)biphenyl-3-yl)-4-methylpentanoic    acid

Example 3212

-   2-(5-chloro-6-(2-methoxyethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic    acid

Example 3213

-   2-(5-chloro-6-(cyclopropylmethoxy)-3′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic    acid

Example 3214

-   2-(5-bromo-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic    acid

Example 3215

-   2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-methylpentanoic    acid

Example 3216

-   2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-phenylpropanoic    acid

Example 3217

-   2-(3-(benzo[d]thiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic    acid

The following examples can also be made using analogous procedures asdescribed previously, substituting the appropriate reagents known tothose of ordinary skill in the art.

Examples 464, 474, 480, 481, 483, 485, 488, 489, 494, 504, 1292, 1334,2490, 2708, 3211, 3212, 3213, 3214, 3215, 3216 and 3217

Pharmacology Experimental

Measurement of AP In Vitro

The Aβ peptide is proteolytically derived from a larger integralmembrane amyloid precursor protein (APP). The production of Aβ isderived from proteolytic cleavages at its N- and C-termini within β-APPby the β and γ-secretase activities, respectively. Transfected cellsoverexpressing β-APP or its equivalent producing the Aβ peptide can beused to monitor the effects of synthetic compounds on the production ofAβ.

To analyze a compound's effects on the concentrations of the variousproducts of the γ-secretase cleavage activity, the Aβ peptides, variousmethods known to a person skilled in the art are available. Examples ofsuch methods, but not limited to, include mass-spectrometricidentification as described by Wang et al, 1996, J. Biol. Chem.271:31894-31902) or detection by specific antibodies using, for example,ELISA's.

Examples of such assays for measuring the production of Aβ_(total), Aβ₄₀and Aβ₄₂ by ELISA include but are not limited to those described byVassar et al., 1999, Science 286:735-741. Suitable kits containing thenecessary antibodies and reagents for such an analysis are available,for example, but not limited to the Genetics Company, Wako, Covance, andInnogenetics. The kits are essentially used according to themanufacturers recommendations similar to the assay that is described byCitron et al., (1997) Nature Medicine 3:67-72 and the original assaydescribed by Seubert et al., (1992) Nature 359:325-327.

Screening was carried out using the human embryonic kidney cell lineHEK-293 overexpressing an amyloid precursor protein (APP) transgenegrown in Pro-293a CDM media (BioWhittaker). Cells were grown toapproximately 70-80% confluency subsequent to the addition of testcompounds. The growth media was aspirated or removed, the cells washed,and replaced with 100 μl of compound, appropriately diluted in serumfree media. The plates are then incubated for 16-18 hours at 37° C.

Conditioned Medium samples are removed for analysis/quantitation of thevarious Aβ peptide levels by differential ELISA's as described inaccompanying instructions to the kits. Those compounds examined which donot demonstrate any overt toxicity or non-specific inhibitory propertiesare investigated further for their Aβ inhibitory effects and form thebasis of medicinal chemistry efforts and to study the effect of thecompounds in different experimental conditions and configurations.

Table 14 shows representative in vitro data (HEK 293) EC₅₀ data forcompounds of the disclosure where:

A indicates a compound has an EC₅₀ for lowering Aβ42 of <1 μM

B indicates a compound has an EC₅₀ for lowering Aβ42 of >1 μM but <5 μM

C indicates a compound has an EC₅₀ for lowering Aβ42 of >5 μM

TABLE 14 Example # Activity 264 A 414 A 415 A 419 A 464 A 474 A 480 A481 A 482 A 483 A 484 A 485 A 488 A 489 A 494 A 504 A 514 A 524 A 534 A554 A 724 A 754 B 1055 A 1268 A 1269 A 1270 A 1271 A 1272 A 1277 A 1280A 1289 A 1292 A 1301 A 1304 A 1313 A 1316 A 1325 A 1334 A 1832 A 1833 A1836 A 1837 A 1904 A 1905 A 1908 A 1909 A 1976 A 2418 A 2419 A 2422 A2423 A 2490 A 2491 A 2494 A 2495 A 2708 A 2959 A 2995 A 3200 A 3201 A3202 B 3203 A 3204 A 3205 A 3206 A 3207 B 3208 A 3209 A 3210 A 3211 A3212 A 3213 A 3214 A 3215 A 3216 A 3217 B

Table 15 shows individual EC₅₀ values for representative compounds ofthe disclosure.

TABLE 15 Example EC₅₀ (Aβ42) # Compounds Name HEK 293 (μM) 4842-(5-chloro-6-(cyclopropylmethoxy)-4′- 0.069(trifluoromethyl)biphenyl-3-yl)-4- methylpentanoic acid 5142-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5- 0.274chloro-4-(cyclopropylmethoxy)phenyl)-4- methylpentanoic acid 29592-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-3- 0.298chloro-5-(2-cyclopropylethyl)phenyl)-4- methylpentanoic acid 29952-(4-(benzo[c][1,2,5]thiadiazol-5-yl)-3- 0.220chloro-5-(2-cyclopropylethyl)phenyl)-4- methylpentanoic acid 32102-(5-cyano-6-(cyclopropylmethoxy)-4′- 0.275(trifluoromethyl)biphenyl-3-yl)-4- methylpentanoic acid

Experimental Procedures for Rat Primary Cortical Culture-Based Abeta₁_(→) _(42/1) _(→) _(x) ELISAs

Rat primary neocortical cultures are established through the dissectionof the neocortices from 10-12 E17 embryos harvested from time-pregnantSD (Sprague Dawley) rats (Charles River Laboratories). Followingdissection, the combined neocortical tissue specimen volume is broughtup to 5 mL with dissection medium (DM; 1×HBSS (Invitrogen Corp.,cat#14185-052)/10 mM HEPES (Invitrogen Corp., cat#15630-080)/1 mM SodiumPyruvate (Invitrogen Corp., cat#11360-070)) supplemented with 100 uLTrypsin (0.25%; Invitrogen Corp., cat#15090-046) and 100 uL DNase I(0.1% stock solution in DM, Roche Diagnostics Corp., cat#0104159),undergoing digestion via incubation at 37° C. for 10 minutes. Digestedtissue is washed once in plating medium (PM; NeuroBasal (InvitrogenCorp., cat#21103-049)/10% Horse Serum (Sigma-Aldrich Co., cat#H1138)/0.5mM L-Glutamine (Invitrogen Corp., cat#25030-081)), then resuspended in afresh 10 mL PM volume for trituration. Trituration consists of 18 cycleswith a 5 mL-serological pipet, followed by 18 cycles with aflame-polished glass Pasteur pipet. The volume is elevated to 50 mL withPM, the contents then passed over a 70 um cell-strainer (BD Biosciences,cat#352350) and transferred directly to a wet-ice bath. The cell-densityis quantified using a hemacytometer, and diluted to allow for theplating of 50000 cells/well/100 uL in pre-coated 96-well PDL-coatedplates (Corning, Inc., cat#3665). Cells are incubated for 4-5 hours at37° C./5% CO₂, after which time the entire volume is exchanged tofeeding medium (FM; NeuroBasal/2% B-27 Serum-free supplement (InvitrogenCorp., cat#17504-044)/0.5 mM L-Glutamine/1% Penicillin-Streptomycin(Invitrogen Corp., cat#15140-122)). The cultures undergo two 50% freshFM exchanges, after 3 days in vitro (DIV3), and again at DIV7.

Human C-terminal recognition-site Abeta₁ _(→) ₄₂ and Rat N-terminalrecognition-site Abeta₁ _(→) _(x) capture-antibodies, diluted 1:300 in0.05M Carbonate-Bicarbonate buffer (Sigma-Aldrich Co., C-3041), are useto coat (100 uL/well) flat-bottomed F96 MicroWell™ (MaxiSorp™ surface)plates (Nalge Nunc International, cat#439454), and incubated overnightat 4° C. for eventual use in the ELISA assay. Compounds to be screenedare solubilized in dimethyl sulphoxide (DMSO, Sigma-Aldrich Co.,cat#15493-8), and further diluted in DMSO in an eight-pointdose-response format. Into 96-well plates, dose-response compounddilutions (1000× the desired final concentration) are stamped out at 2uL/well, in duplicate (up to 3 compounds/plate), as a daughter plate. Inaddition, DMSO andN—[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester(DAPT), a gamma-secretase inhibitor (GSI), are incorporated as solventand positive controls, respectively. With the assistance ofliquid-handling automation, the compound daughter plate is diluted 1:500with warmed FM, and two DIV8 culture plates are leveled to 60 uL/well,and immediately overlaid with 60 uL/well of the 2× diluted daughterplate. The plates are returned to the 37° C./5% CO₂-incubator for 24hours.

Each coated capture-antibody ELISA plate undergoes 4×250 uL/wellPhosphate-buffered saline with 0.05% Tween®-20 SigmaUltra (PBS-T; Fluka,cat#79383/Sigma-Aldrich Co., cat#P7949) washes. The ELISA plates arethen overlaid with 120 uL/well PBS-T supplemented with 1% Bovine SerumAlbumin Diluent/Blocking solution (BSA; Kirkegaard & Perry Laboratories(KPL), Inc., cat#50-61-01) and incubate at room-temperature on anorbital shaker for a minimum of 2 hours.

Rat Abeta₁ _(→) ₄₂ and rat Abeta₁ _(→) ₄₀ peptide (American Peptide Co.,cat#62-0-84/62-0-86A) DMSO stock solutions are serially-diluted 1:2 inFM yielding a final concentration range of 0-500 pg/mL, to be plated onthe respective ELISA plates for determination of the correspondingstandard curve, from which concentrations of specific or total Abetapeptides in the presence of a particular drug concentration can becalculated. The conditioned medium from the duplicate culture plates arecollected and combined into one round-bottom 96-well transfer platewhich is incubated on wet-ice. The culture plates are rinsed once with120 ul/well FM, and replenished immediately with 100 uL/well FM, beingreturned to the incubator for 10 minutes. Cell-viability is evaluated byadding 20 uL/well of warmed CellTiter 96® Aq_(ueous) One Solution(MTS/PES; Promega Corp., cat#G3581), and returning the plates to theincubator for 30-90 minutes. Plate absorbance at 492 nm is read on aspectrophotometer, and from which, the ratio of absorbance ofcompound-treated cells to absorbance of solvent (DMSO)-treated controlcells is calculated. The calculation of the corresponding EC₅₀ values isperformed following non-linear curve-fitting using GraphPad Prism®software.

For each ELISA plate, a corresponding transfer-plate is createdcontaining 120 uL/well of either the rat Abeta₁ _(→) ₄₂ or rat Abeta₁_(→) ₄₀ peptide standard solutions, in duplicate, and 110-115 uL/well ofthe collected conditioned-medium plate, half designated for the Abeta₁_(→) ₄₂ ELISA, and the other half for the Abeta₁ _(→) _(x) ELISA. TheELISA plates undergo a second set of 4×250 uL/well PBS-T washes,immediately followed by being overlaid with their designatedtransfer-plate. The ELISA plates incubate on an orbital-shaker for 16-18hours at 4° C.

Detection antibody solution is prepared by diluting beta-Amyloid 17-24(4G8) biotinylated monoclonal antibody (Covance, Inc.,cat#SIG-39240-200) 1:1500 in PBS-T supplemented with 0.67% BSA. TheELISA plates undergo 4×250 uL/well PBS-T washes, and are overlaid with100 uL/well of 4G8 diluted detection-antibody solution. The Abeta₁ _(→)₄₂ ELISA plates are incubated on an orbital-shaker at room-temperaturefor 90 minutes, the Abeta₁ _(→) _(x) ELISA plates for 60 minutes.

In order to conjugate the biotinylated monoclonal 4G8 antibody,following 4×250 uL/well PBS-T washes, the ELISA plates undergo aone-hour incubation at 100 ul/well with a 1:15000 dilution ofStreptavidin-HRP conjugate (Jackson ImmunoResearch Laboratories, Inc.,cat#016-030-0840) on an orbital-shaker at room temperature.

Following a final set of 4×250 uL/well PBS-T washes, the ELISA platesare overlaid with 100 ul/well SureBlue 3,3′,5,5′-Tetramethylbenzidine(TMB) Microwell Peroxidase substrate solution (Kirkegaard & PerryLaboratories, Inc., cat#52-00-02), protected from light, and incubatefor 20-45 minutes at room temperature. At the point the desired level ofdevelopment is attained, 100 ul/well of TMB Stop solution (Kirkegaard &Perry Laboratories, Inc., cat#50-85-05) is added, and the platethoroughly shaken in preparation for reading on a spectrophotometer.SureBlue TMB Microwell Substrate develops a deep blue color in thepresence of a peroxidase-labeled conjugate, and turns yellow whenstopped by acidification, allowing for plate absorbance at 450 nm to beread. From the calculation of the standard curve, the compounddose-response curves, normalized to DAPT performance, are plotted as %DMSO using GraphPad Prism® software, and the corresponding EC₅₀ valuescalculated.

Measurement of Aβ 42 In Vivo

Compounds of the invention can be used to treat AD in mammal such as ahuman or alternatively in a validated animal model such as the mouse,rat, or guinea pig. The mammal may not be diagnosed with AD, or may nothave a genetic predisposition for AD, but may be transgenic such that itoverproduces and eventually deposits Aβ in a manner similar to that seenin the human. Additionally, non-transgenic animals may also be used todetermine the biochemical efficacy of the compound, with an appropriateassay.

Compounds can be administered in any standard form using any standardmethod. For example, but not limited to, compounds can be in the form ofliquid, tablets or capsules that are taken orally or by injection.Compounds can be administered at any dose that is sufficient tosignificantly reduce, for example, levels of Aβ_(tota) or morespecifically Aβ₃₄₂ in the blood plasma, cerebrospinal fluid (CSF), orbrain.

To determine whether acute administration of the compound would reduceAβ₄₂ levels in-vivo, two-three month old Tg2576 transgenic miceexpressing APP₆₉₅ containing the “Swedish” variant could be used or anyother appropriately validated transgenic model. This transgenic mousedisplays spontaneous, progressive accumulation of β-amyloid (Aβ) inbrain, eventually resulting in amyloid plaques within the subiculum,hippocampus and cortex. Animals of this age have high levels of Aβ inthe brain but no detectable Aβ deposition. Mice treated with thecompound would be examined and compared to those untreated or treatedwith vehicle and brain levels of soluble Aβ42 and total Aβ would bequantitated by standard techniques, for example, using ELISA. Treatmentsmay be acute or sub-chronic and treatment periods may vary from hours todays or longer and can be adjusted based on the results of thebiochemical endpoint once a time course of onset of effect can beestablished.

A typical protocol for measuring Aβ or Aβ₄₂ levels from in-vivo samplesis shown but it is only one of many variations that could used to detectthe levels of Aβ. For example, aliquots of compounds can be dissolved inDMSO (volume equal to 1/10th of the final formulation volume), vortexedand further diluted (1:10) with a 10% (w/v) hydroxypropyl β cyclodextrin(HBC, Aldrich, Ref N^(o) 33, 260-7) solution in PBS, where after theyare sonicated for 20 seconds.

-   -   Compounds may be administered as a single oral dose given three        to four hours before sacrifice and subsequent analysis or        alternatively could be given over a course of days and the        animals sacrificed three to four hours after the administration        of the final dose    -   Tg2576 mice can be anesthetized with a mixture of        ketamine/xylazine (80/16 mg/kg intraperitoneally). When a deep        level of anesthesia is reached, the mouse's head is secured in a        stereotaxic frame. The skin on the back of the neck is retracted        and the muscles on the back of the neck are removed to expose        the cisterna magna. CSF is collected from the cisterna magna        using a pulled 10 μl micropipette taking care not to contaminate        the CSF with blood. The CSF is immediately diluted 1:10 in 1%        3-[3-cholamidopropyl)-dimethyl-ammonio]-1-propane sulfonate        (CHAPS) [weight per volume in phosphate buffered saline (w/v in        PBS)] containing protease inhibitors (PI's) (Complete, Mini        protease inhibitor cocktail tablets-Roche), quick frozen in        liquid nitrogen and stored at −80° C. until ready for        biochemical analysis.

Blood is collected via cardiac puncture using a 25 gauge needle attachedto a 1 ml syringe and was dispensed into a 0.6 ml microtainer tubecontaining ethylenediaminetetraacetic acid (EDTA). The blood wascentrifuged immediately at 4° C. for 5 minutes at 1500×G. The resultingplasma was aliquoted into 0.5 ml microcentrifuge tubes, the aliquots arequick frozen in liquid nitrogen and are stored at −80° C.

The brain is removed after removing the skull and is rinsed with PBS.The cerebellum/brain-stem is removed, frozen, and retained for drugexposure analysis; the remaining brain section was quartered. The rearright quarter, which contained cortex and hippocampus, is weighed,frozen in liquid nitrogen and stored at −80° C. until ELISA analysis.The remaining brain tissue is frozen in liquid nitrogen and stored at−80° C.

For total Aβ or Aβ₄₀ analysis brain tissue is homogenized at a volume of24 ml/g in cold 1% CHAPS containing protease inhibitors and theresulting homogenates are centrifuged for 1 hour at 100,000×g at 4° C.The supernatant is removed and transferred to a fresh tube and furtherdiluted to 240 ml/g in CHAPS with protease inhibitors.

For Aβ₄₂ analysis brain tissue is homogenized at a volume of 50 ml/g incold 1% CHAPS containing PI's. Homogenates were spun for 1 hour at100,000×g at 4° C. The supernatant is removed and transferred to a freshtube and further to diluted to a final volume 66.7 ml/g in 1% CHAPS withprotease inhibitors.

To quantify the amount of human Aβ₄₂ in the soluble fraction of thebrain homogenates, commercially availableEnzyme-Linked-Immunosorbent-Assay (ELISA) kits can be used (h AmyloidAβ42 ELISA high sensitive, The Genetics Company, Zurich, Switzerland isjust one of many examples). The ELISA is performed according to themanufacturer's protocol. Briefly, the standard (a dilution of syntheticAβ1-42) and samples are prepared in a 96-well polypropylene platewithout protein binding capacity (Greiner bio-one, Frickenhausen,Germany). The standard dilutions with final concentrations of 1000, 500,250, 125, 62.5, 31.3 and 15.6 pg/ml and the samples are prepared in thesample diluent, furnished with the ELISA kit, to a final volume of 60μl. Samples, standards and blanks (50 μl) are added to theanti-Aβ-coated polystyrol plate (capture antibody selectively recognizesthe C-terminal end of the antigen) in addition with a selectiveanti-Aβ-antibody conjugate (biotinylated detection antibody) andincubated overnight at 4° C. in order to allow formation of theantibody-Amyloid-antibody-complex. The following day, aStreptavidine-Peroxidase-Conjugate is added, followed 30 minutes laterby an addition of TMB/peroxide mixture, resulting in the conversion ofthe substrate into a colored product. This reaction is stopped by theaddition of sulfuric acid (1M) and the color intensity is measured bymeans of photometry with an ELISA-reader with a 450 nm filter.Quantification of the Aβ content of the samples is obtained by comparingabsorbance to a standard curve made with synthetic Aβ1-42.

Similar analysis, with minor modification, can be carried out with CSF(Diluted 1:10 (for a final loading dilution of 1:100) in 1% CHAPScontaining PI and plasma samples (Diluted 1:15 in 0.1% CHAPS [w/v inPBS]).

Certain compounds of the disclosure may lower Aβ42 by >15%, in somecases certain compounds may lower Aβ42>25% and in further cases certaincompounds may lower Aβ42>40% relative to basal levels.

In Vivo Studies (Rats)

Male Sprague Dawley rats from Harlan, 230-350 g, were used for studies.Fasted rats were dosed via oral gavage, with vehicle (15% Solutol HS 15,10% EtOH, 75% Water) or compound, at a volume of 10 ml/kg. For PKstudies, at fixed time points after dosing, the rats were euthanizedwith an excess of CO₂. Terminal blood was collected through cardiacpuncture, mixed in EDTA tubes, immediately spun (3 min at 11,000 rpm at4° C.), and snap frozen for plasma collection. A piece of frontal cortexwas collected and snap frozen for compound level determination. ForA-beta lowering studies, at a determined time point after dosing (Cmaxif it is ≧3 hr), rats were euthanized as in the PK studies and plasmawas collected as described above. Cerebellum was removed and saved forcompound level determination, and the remaining brain was divided into 4quadrants, snap frozen and saved to examine A-beta peptide levels.Solutol HS 15 was purchased from Mutchler Inc.

Practitioners will also know that similar methods can also be applied toother species such as mice (including transgenic strains such asTg2576), guinea pig, dog and monkey.

Analysis of In Vivo Aβ Lowering Studies

Compounds of the invention can be used to treat AD in mammal such as ahuman or alternatively in a validated animal model such as the mouse,rat, or guinea pig. The mammal may not be diagnosed with AD, or may nothave a genetic predisposition for AD, but may be transgenic such that itoverproduces and eventually deposits Aβ in a manner similar to that seenin the human. Alternatively, non-transgenic animals may also be used todetermine the biochemical efficacy of the compound, that is, the effecton the Aβ biomarker, with an appropriate assay.

Compounds can be administered in any standard form using any standardmethod. For example, but not limited to, compounds can be in the form ofliquid, tablets or capsules that are taken orally or by injection.Compounds can be administered at any dose that is sufficient tosignificantly reduce, for example, levels of Aβ_(total) or morespecifically Aβ₄₂ in the blood plasma, cerebrospinal fluid (CSF), orbrain.

To determine whether acute administration of the compound would reduceAβ₄₂ levels in-vivo, two-three month old non-transgenic Sprague-Dawleyrats were used. Rats treated with the compound would be examined andcompared to those untreated or treated with vehicle and brain levels ofsoluble Aβ₄₂ and Aβ_(total) would be quantitated by standard techniques,for example, using an immunoassay such as an ELISA. Treatments may beacute or sub-chronic and treatment periods may vary from hours to daysor longer and can be adjusted based on the results of the biochemicalendpoint once a time course of onset of effect can be established.

A typical protocol for measuring Aβ or Aβ₄₂ levels from in-vivo samplesis shown but it is only one of many variations that could used to detectthe levels of Aβ.

-   -   Compounds may be administered as a single oral dose given three        to four hours before sacrifice and subsequent analysis or        alternatively could be given over a course of days and the        animals sacrificed three to four hours after the administration        of the final dose.

For total Aβ or Aβ₄₂ analysis brain tissue is homogenized in ten volumesof ice cold 0.4% DEA/50 mM NaCl containing protease inhibitors, e.g.,for 0.1 g of brain 1 ml of homogenization buffer is added.Homogenization is achieved either by sonciation for 30 seconds at 3-4Wof power or with a polytron homogenizer at three-quarters speed for10-15 seconds. Homogenates (1.2 ml) are transferred to pre-chilledcentrifuge tubes (Beckman 343778 polycarbonate tubes) are placed into aBeckman TLA20.2 rotor. Homogenates are centrifuged for 1 hour at 100,000rpm (355,040×g) at 4° C. The resulting supernatants are transferred tofresh sample tubes and placed on ice (the pellets are discarded).

The samples are further concentrated and purified by passage over Waters60 mg HLB Oasis columns according to the methods described (Lanz andSchachter (2006) J. Neurosci Methods. 157(1):71-81; Lanz and Schachter(2008). J. Neurosci Methods. 169(1):16-22). Briefly, using a vacuummanifold (Waters#WAT200607) the columns are attached and conditionedwith 1 ml of methanol at a flow rate of 1 ml/minute. Columns are thenequilibrated with 1 ml of water. Samples are loaded (800 μl) intoindividual columns (the Aβ will attach to the column resin). The columnsare washed sequentially with 1 ml of 5% methanol followed by 1 ml of 30%methanol. After the final wash the eluates are collected in 13×100 mmtubes by passing 800 μl of solution of 90% methanol/2% ammoniumhydroxide) over the columns at 1 ml/minute. The samples are transferredto 1.5 ml non-siliconized sample tubes are dried in a speed-vacconcentrator at medium heat for at least 2 hours or until dry.

The dried samples are either stored at −80° C. or are used immediatelyby resuspending the pellets in 80 μl of Ultra-Culture serum-free media(Lonza) supplemented with protease inhibitors by vortexing for 10seconds. Sixty microliters of each sample is transferred to a pre-coatedimmunoassay plate coated with an affinity purified rabbit polyclonalantibody specific to Aβ₄₂ (x-42). Sixty microliters of freshsupplemented ultraculture is added to the remaining sample and 60microliters is transferred to a pre-coated and BSA blocked immunoassayplate coated with an affinity purified rabbit polyclonal antibodyspecific to total rodent Aβ (1-x). Additional standard samples of rodentAβ/rodent Aβ₄₂ are also added to the plates with final concentrations of1000, 500, 250, 125, 62.5, 31.3 and 15.6 pg/ml. The samples areincubated overnight at 4° C. in order to allow formation of theantibody-Amyloid-antibody-complex. The following day the plates arewashed 3-4 times with 150 microliters of phosphate buffered salinecontaining 0.05% Tween 20. After removal of the final wash 100 μl of themonoclonal antibody 4G8 conjugated to biotin (Covance) diluted 1:1000 inPBS-T containing 0.67% BSA was added and the plates incubated at roomtemperature for 1-2 hours. The plates are again washed 3-4 times withPBS-T and 100 μl of a Streptavidin-Peroxidase-Conjugate diluted 1:10,000from a 0.5 mg/ml stock in PBS-T contained 0.67% BSA is added and theplates incubated for at least 30 minutes. Following a final set ofwashes in PBS-T, a TMB/peroxide mixture is added, resulting in theconversion of the substrate into a colored product. This reaction isstopped by the addition of sulfuric acid (1M) and the color intensity ismeasured by means of photometry with an microplate reader with a 450 nmfilter. Quantification of the Aβ content of the samples is obtained bycomparing absorbance to a standard curve made with synthetic Aβ. This isone example of a number of possible measurable endpoints for theimmunoassay which would give similar results.

FIG. 1 demonstrates the desirable effect on Aβ after the administrationof example 1301(2-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoicacid) to in C57BL/6 mice when give one dose at 30 mg/kg in a SolutolHS15:Ethanol:Water (15:10:75) formulation (measuring Aβ at 3 hours).

Pharmacokinetic Analysis

Sample Preparation

Plasma samples and standards were prepared for analysis by treating witha 3× volume of acetonitrile containing 500 ng/mL of internal standard (aselected aryl propionic acid). Typically 150 μL of acetonitrile withinternal standard was added to 50 μL of plasma. Acetonitrile was addedfirst to each well of a 96-well Phenomenex Strata Impact proteinprecipitation filter plate followed by the addition of the plasma sampleor standard. The filter plate was allowed to sit for at least 15 minutesat room temperature before a vacuum was applied to filter the samplesinto a clean 96-well plate.

If sample concentrations were observed or predicted to be greater than1000 ng/mL, plasma samples were diluted with blank plasma 10-150 folddepending on the anticipated concentration and upper limit ofquantitation of the analytical method.

Samples of frontal cortex or cerebellum were homogenized then treated insimilar manner. To each brain sample, a 4× volume of PBS (pH 7.4) bufferwas added along with a 15× volume of acetonitrile (containing internalstandard) in a 2 mL screw-cap plastic tube. The tubes were then filledone third of the way with 1 mm zirconia/silica beads (Biospec) andplaced in a Mini Bead Beater for 3 minutes. The samples were inspectedand if any visible pieces of brain remained, they were returned to theBead Beater for another 2-3 minutes of shaking. The resulting suspensionwas considered to be a 5-fold dilution treated with a 3× volume ofacetonitrile (with internal standard). Calibration standards wereprepared in 5-fold diluted blank brain homogenate and precipitated witha 3× volume of acetonitrile immediately after the addition of theappropriate spiking solution (see below). All brain standards andsamples were allowed to sit for at least 15 minutes prior to filteringthem through a Phenomenex Strata Impact protein precipitation filterplate into a clean 96-well plate.

Spiking solutions for plasma and brain calibration standards wereprepared at concentrations of 0.02, 0.1, 0.2, 1, 2, 10, 20, 100 and 200μg/mL in 50:50 acetonitrile/water. Calibration standards were preparedby taking 190 μL of blank matrix (plasma or brain homogenate) and adding10 μL of spiking solution resulting in final concentrations of 1, 5, 10,50, 100, 500, 1000, 5000 and 10,000 ng/mL.

LC-MS/MS Analysis

Precipitated plasma and brain samples were analyzed by LC-MS/MS using aShimadzu LC system consisting of two LC-10AD pumps and a SIL-HTcautosampler connected to an Applied Biosystems MDS/Sciex API 3200 QTRAPmass spectrometer.

For chromatographic separation, a Phenomenex Luna C-18 3 μM (2×20 mm)column was used with an acetonitrile-based gradient mobile phase. Thetwo mobile phase components were:

Mobile phase A: water with 0.05% (v/v) formic acid and 0.05% (v/v) 5 Nammonium hydroxide.

Mobile phase B: 95:5 acetonitrile/water with 0.05% (v/v) formic acid and0.05% (v/v) 5 N ammonium hydroxide.

The gradient for each analysis was optimized for the specific compound,but generally, the run started with between 0% and 40% of mobile phaseB, ramped up to 100% of mobile phase B over 1-2 minutes, then held therefor 2-3 minutes before returning to the initial conditions for 4 minutesto re-equilibrate.

The API 3200 QTRAP mass spectrometer was used in MRM mode with negativeelectrospray ionization. MRM transitions and mass spec settings wereoptimized for each compound.

Standard curves were created by quadratic or linear regression with1/x*x weighting. Calibration standards were prepared 1-10,000 ng/mL, butthe highest (and sometimes lowest) standards were often not acceptablefor quantitation and only those standards with reasonableback-calculated accuracies were included in the calibration curve.Ideally, only standards with +/−15% of nominal concentration would beincluded in the fitted standard curve, but occasionally largerdeviations were accepted after careful consideration. Sampleconcentrations below the quantitation range were reported as “BQL”.Concentrations above the curve were usually re-run with larger sampledilutions

Glucuronidation Protocols

Microsomal glucuronidation reactions were conducted using the UGTReaction Mix solutions (A and B) from BD Biosciences and following thevendor's protocol. 10 μM of test article or control compound wasincubated with 0.5 mg/mL of human or rat liver microsomes. Samples weretaken at 0 and 60 minutes and acetonitrile was added to terminate thereactions. Samples were analyzed by LC/MS, monitoring for the loss ofparent compound and the appearance of glucuronide. Control reactionswere run for each compound substituting water for the glucuronic acidsolution to monitor for any loss of parent compound due to degradationor unanticipated micro somal reactions.

Hepatocyte experiments were run using cryopreserved human hepatocytes(single donor) obtained from Celsis/In Vitro Technologies. Cells werethawed and counted according to the vendor's protocols using the trypanblue exclusion method to obtain the count of live cells. Test articleand control compounds were incubated at a concentration of 5 uM in KHBbuffer (Celsis/In Vitro Technologies) containing 1 million cells per mL.Samples were taken at 0, 60 and 120 minutes. The reactions wereterminated with addition of acetonitrile. Samples were analyzed byLC/MS, monitoring for the loss of parent compound and the appearance ofglucuronide.

Pharmacology

Compounds of the disclosure are gamma secretase modulators (GSMs), i.e.,compounds that act to shift the relative levels of Aβ peptides producedby γ-secretase. In some cases the compounds alter the relative levels ofAβ peptides produced by γ-secretase without significantly changing thetotal level of Aβ peptides produced. Certain compounds of the disclosuremodulate γ-secretase activity with respect to APP proteolytic processingand in so doing lower the production of Aβ₄₂ both in vitro in cells andin vivo in animals. In some cases this effect occurs at concentrationsthat do not significantly impair the viability of cells in vitro and atdoses that are well tolerated in vivo. Certain compounds of thedisclosure lower Aβ₄₂ secretion in native neuronal and cellularconstruct assay systems with EC₅₀ values that are below 1 micromolar(Class A compounds, Table 14) while others have EC₅₀ values from 1-5micromolar (Class B compounds, Table 14) and others have EC₅₀ valuesgreater than 5 micromolar (Class C compounds). Certain compounds of thedisclosure do not appear to significantly interfere with γ-secretaserelated Notch processing activity. Compounds that significantlyinterfere with γ-secretase related Notch processing activity have beenassociated with toxic side-effects. Certain compounds of the disclosurehave favorable pharmacokinetic (PK) properties in animals. Thus, certainof the compounds are orally bioavailable, penetrate into the brain andhave favorable PK parameters including half-life and clearancesupporting pharmaceutical application in humans. In turn, certaincompounds of the disclosure significantly lower Aβ₄₂ production in thebrains of non-transgenic and transgenic animals after single dose andmulti-dose oral administration with no overt side effects. For certaincompounds of the disclosure single oral doses of <30 milligrams/kilogramare efficacious at lowering Aβ₄₂ production in the brains of rats (e.g.Sprague-Dawley) and wild type mice (e.g. C57BL/6). Certain compounds ofthe disclosure which lower Aβ₄₂ at doses of <30 milligrams/kilogramappear to be well tolerated and show no overt or clinical chemicaltoxicity after subchronic 14-day administration at doses >30milligrams/kilogram/day. Certain compounds of the disclosure havefavorable absorption-distribution-metabolism and excretion (ADME)properties. Moreover, certain compounds of the disclosure do not appearto significantly bio-accumulate in tissues especially in the brain.Compounds of Formulas I-IX wherein A=CO₂H show favorable profiles withrespect to acylglucoronide (A=CO₂Glu) metabolite formation. Thepotential for acylglucoronide metabolites to cause of toxicity has beendescribed particularly for non-steroidal anti-inflammatory drugs(NSAIDs) containing carboxylic acid groups (Ebner et at Drug Metabolismand Disposition 1999, 27(10),1143-49). Several such NSAIDs have beenremoved from the market due to idiosyncratic toxicity in humans and ithas been speculated that NSAID idiosyncratic toxicity is related to therelative load and relative reactivity of acylglucoronide metabolites.Therefore, carboxylic acid compounds which are less prone toacylgluconoride formation are expected to be less toxic. As measuredusing established in vitro assay systems, certain desirable compounds ofthe disclosure are less prone to acylglucoronidation than NSAIDcompounds that remain on the market are regarded as safe (e.g.,flurbiprofen).

Dosage and Administration

The present disclosure includes pharmaceutical composition for treatinga subject having a neurological disorder comprising a therapeuticallyeffective amount of a compound of Formulas I-IX, a derivative or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, carrier or diluent.

The pharmaceutical compositions can be administered in a variety ofdosage forms including, but not limited to, a solid dosage form or in aliquid dosage form, an oral dosage form, a parenteral dosage form, anintranasal dosage form, a suppository, a lozenge, a troche, buccal, acontrolled release dosage form, a pulsed release dosage form, animmediate release dosage form, an intravenous solution, a suspension orcombinations thereof. The dosage can be an oral dosage form that is acontrolled release dosage form. The oral dosage form can be a tablet ora caplet. The compounds can be administered, for example, by oral orparenteral routes, including intravenous, intramuscular,intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal,vaginal and topical (including buccal and sublingual) administration. Inone embodiment, the compounds or pharmaceutical compositions comprisingthe compounds are delivered to a desired site, such as the brain, bycontinuous injection via a shunt.

In another embodiment, the compound can be administered parenterally,such as intravenous (i.v.) administration. The formulations foradministration will commonly comprise a solution of the compound of theFormulas I-IX dissolved in a pharmaceutically acceptable carrier. Amongthe acceptable vehicles and solvents that can be employed are water andRinger's solution, an isotonic sodium chloride. In addition, sterilefixed oils can conventionally be employed as a solvent or suspendingmedium. For this purpose any bland fixed oil can be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid can likewise be used in the preparation of injectables. Thesesolutions are sterile and generally free of undesirable matter. Theseformulations may be sterilized by conventional, well known sterilizationtechniques. The formulations may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionssuch as pH adjusting and buffering agents, toxicity adjusting agents,e.g., sodium acetate, sodium chloride, potassium chloride, calciumchloride, sodium lactate and the like. The concentration of compound ofFormulas I-IX in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For i.v. administration, theformulation can be a sterile injectable preparation, such as a sterileinjectable aqueous or oleaginous suspension. This suspension can beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationcan also be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In one embodiment, a compound of Formulas I-IX can be administered byintroduction into the central nervous system of the subject, e.g., intothe cerbrospinal fluid of the subject. The formulations foradministration will commonly comprise a solution of the compound ofFormulas I-IX dissolved in a pharmaceutically acceptable carrier. Incertain aspects, the compound of Formulas I-IX is introducedintrathecally, e.g., into a cerebral ventricle, the lumbar area, or thecisterna magna. In another aspect, the compound of Formulas I-IX isintroduced intraocullarly, to thereby contact retinal ganglion cells.

The pharmaceutically acceptable formulations can easily be suspended inaqueous vehicles and introduced through conventional hypodermic needlesor using infusion pumps. Prior to introduction, the formulations can besterilized with, preferably, gamma radiation or electron beamsterilization.

In one embodiment, the pharmaceutical composition comprising a compoundof Formulas I-IX is administered into a subject intrathecally. As usedherein, the term “intrathecal administration” is intended to includedelivering a pharmaceutical composition comprising a compound ofFormulas I-IX directly into the cerebrospinal fluid of a subject, bytechniques including lateral cerebroventricular injection through aburrhole or cisternal or lumbar puncture or the like (described inLazorthes et al. Advances in Drug Delivery Systems and Applications inNeurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1:169-179, the contents of which are incorporated herein by reference).The term “lumbar region” is intended to include the area between thethird and fourth lumbar (lower back) vertebrae. The term “cisternamagna” is intended to include the area where the skull ends and thespinal cord begins at the back of the head. The term “cerebralventricle” is intended to include the cavities in the brain that arecontinuous with the central canal of the spinal cord. Administration ofa compound of Formulas I-IX to any of the above mentioned sites can beachieved by direct injection of the pharmaceutical compositioncomprising the compound of Formulas I-IX or by the use of infusionpumps. For injection, the pharmaceutical compositions can be formulatedin liquid solutions, preferably in physiologically compatible bufferssuch as Hank's solution or Ringer's solution. In addition, thepharmaceutical compositions may be formulated in solid form andre-dissolved or suspended immediately prior to use. Lyophilized formsare also included. The injection can be, for example, in the form of abolus injection or continuous infusion (e.g., using infusion pumps) ofpharmaceutical composition.

In one embodiment, the pharmaceutical composition comprising a compoundof Formulas I-IX is administered by lateral cerebro ventricularinjection into the brain of a subject. The injection can be made, forexample, through a burr hole made in the subject's skull. In anotherembodiment, the encapsulated therapeutic agent is administered through asurgically inserted shunt into the cerebral ventricle of a subject. Forexample, the injection can be made into the lateral ventricles, whichare larger, even though injection into the third and fourth smallerventricles can also be made.

In yet another embodiment, the pharmaceutical composition isadministered by injection into the cisterna magna, or lumbar area of asubject.

For oral administration, the compounds will generally be provided inunit dosage forms of a tablet, pill, dragee, lozenge or capsule; as apowder or granules; or as an aqueous solution, suspension, liquid, gels,syrup, slurry, etc. suitable for ingestion by the patient. Tablets fororal use may include the active ingredients mixed with pharmaceuticallyacceptable excipients such as inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate, and lactose,while corn starch and alginic acid are suitable disintegrating agents.Binding agents may include starch and gelatin, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be coated with a material such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract.

Pharmaceutical preparations for oral use can be obtained throughcombination of a compound of Formulas I-IX with a solid excipient,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable additional compounds, if desired, toobtain tablets or dragee cores. Suitable solid excipients in addition tothose previously mentioned are carbohydrate or protein fillers thatinclude, but are not limited to, sugars, including lactose, sucrose,mannitol, or sorbitol; starch from corn, wheat, rice, potato, or otherplants; cellulose such as methyl cellulose,hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gumsincluding arabic and tragacanth; as well as proteins such as gelatin andcollagen. If desired, disintegrating or solubilizing agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, alginicacid, or a salt thereof, such as sodium alginate.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredients is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

For transmucosal administration (e.g., buccal, rectal, nasal, ocular,etc.), penetrants appropriate to the barrier to be permeated are used inthe formulation. Such penetrants are generally known in the art.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate. Formulations suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing in addition to the active ingredient suchcarriers as are known in the art to be appropriate. For intramuscular,intraperitoneal, subcutaneous and intravenous use, the compounds willgenerally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity. Suitable aqueous vehiclesinclude Ringer's solution and isotonic sodium chloride. Aqueoussuspensions may include suspending agents such as cellulose derivatives,sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wettingagent such as lecithin. Suitable preservatives for aqueous suspensionsinclude ethyl and n-propyl p-hydroxybenzoate.

The suppositories for rectal administration of the drug can be preparedby mixing the drug with a suitable non-irritating excipient which issolid at ordinary temperatures but liquid at the rectal temperatures andwill therefore melt in the rectum to release the drug. Such materialsare cocoa butter and polyethylene glycols.

The compounds can be delivered transdermally, by a topical route,formulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.

The compounds may also be presented as aqueous or liposome formulations.Aqueous suspensions can contain a compound of Formulas I-IX in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions can be formulated by suspending a compound of FormulasI-IX in a vegetable oil, such as arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin; or a mixtureof these. The oil suspensions can contain a thickening agent, such asbeeswax, hard paraffin or cetyl alcohol. Sweetening agents can be addedto provide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil or a mineral oil,described above, or a mixture of these. Suitable emulsifying agentsinclude naturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening agents and flavoring agents, as inthe formulation of syrups and elixirs. Such formulations can alsocontain a demulcent, a preservative, or a coloring agent.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation or transcutaneous delivery (e.g.,subcutaneously or intramuscularly), intramuscular injection or atransdermal patch. Thus, for example, the compounds may be formulatedwith suitable polymeric or hydrophobic materials (e.g., as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

For administration by inhalation, the compounds are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g., gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In general a suitable dose will be in the range of 0.01 to 100 mg perkilogram body weight of the recipient per day, preferably in the rangeof 0.2 to 10 mg per kilogram body weight per day. The desired dose ispreferably presented once daily, but may be dosed as two, three, four,five, six or more sub-doses administered at appropriate intervalsthroughout the day.

The compounds can be administered as the sole active agent, or incombination with other known therapeutics to be beneficial in thetreatment of neurological disorders. In any event, the administeringphysician can provide a method of treatment that is prophylactic ortherapeutic by adjusting the amount and timing of drug administration onthe basis of observations of one or more symptoms (e.g., motor orcognitive function as measured by standard clinical scales orassessments) of the disorder being treated.

Details on techniques for formulation and administration are welldescribed in the scientific and patent literature, see, e.g., the latestedition of Remington's Pharmaceutical Sciences, Maack Publishing Co,Easton Pa. (“Remington's After a pharmaceutical composition has beenformulated in an acceptable carrier, it can be placed in an appropriatecontainer and labeled for treatment of an indicated condition. Foradministration of the compounds of Formulas I-IX, such labeling wouldinclude, e.g., instructions concerning the amount, frequency and methodof administration.

1. A method for the therapeutic treatment of Alzheimer's diseasecomprising administering to a patient in need thereof an effectiveamount of(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoicacid or a pharmaceutically acceptable salt thereof.
 2. A method for thetherapeutic treatment of Alzheimer's disease comprising administering toa patient in need thereof an effective amount of(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoicacid or a pharmaceutically acceptable salt thereof.
 3. A method for thetherapeutic treatment of Alzheimer's disease comprising administering toa patient in need thereof an effective amount of a pharmaceuticalcomposition comprising:(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoicacid or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier or excipient.
 4. The method of claim3, wherein the pharmaceutical composition is in a solid dosage form. 5.The method of claim 3, wherein the pharmaceutical composition is in anoral dosage form.
 6. The method of claim 5, wherein the oral dosage formis a tablet or a capsule.
 7. The method of claim 6, wherein the oraldosage form is a tablet.
 8. A method for the therapeutic treatment ofAlzheimer's disease comprising administering to a patient in needthereof an effective amount of a pharmaceutical composition comprising:(S)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoicacid or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier or excipient.
 9. The method of claim8, wherein the pharmaceutical composition is in a solid dosage form. 10.The method of claim 8, wherein the pharmaceutical composition is in anoral dosage form.
 11. The method of claim 10, wherein the oral dosageform is a tablet or a capsule.
 12. The method of claim 11, wherein theoral dosage form is a tablet.